malaria vaccine research paper

• Open access
• Published: 23 November 2020

Building momentum for malaria vaccine research and development: key considerations

• Chetan E. Chitnis 1 ,
• David Schellenberg   ORCID: orcid.org/0000-0001-8222-0186 2 ,
• Johan Vekemans 2 ,
• Edwin J. Asturias 3 ,
• Philip Bejon 4 ,
• Katharine A. Collins 5 ,
• Brendan S. Crabb 6 ,
• Socrates Herrera 7 ,
• Miriam Laufer 8 ,
• N. Regina Rabinovich 9 , 10 ,
• Meta Roestenberg 11 ,
• Adelaide Shearley 12 ,
• Halidou Tinto 13 ,
• Marian Wentworth 14 ,
• Kate O’Brien 2 &
• Pedro Alonso 2  

Malaria Journal volume  19 , Article number:  421 ( 2020 ) Cite this article

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To maintain momentum towards improved malaria control and elimination, a vaccine would be a key addition to the intervention toolkit. Two approaches are recommended: (1) promote the development and short to medium term deployment of first generation vaccine candidates and (2) support innovation and discovery to identify and develop highly effective, long-lasting and affordable next generation malaria vaccines.

In what is a truly great public health success story, expanded efforts to control and eliminate malaria have effectively halved malaria incidence and mortality since 2000. Several million lives have been saved in that time and a number of previously endemic countries in Asia, South and Central America and Africa have been formally declared malaria free.

This astonishing success has been achieved with a limited toolkit, largely comprising methods to prevent transmission by the mosquito vector through the use of insecticide-treated bed nets and indoor residual spraying, the use of chemoprevention in specific, vulnerable groups, and effective chemotherapy following rapid point-of-care diagnosis. Current vector control and effective anti-malarial treatment strategies represent significant success in both product development and implementation science.

However, progress in areas with high transmission has slowed and further reduction in malaria incidence and deaths has stalled in recent years. The 2018 and 2019, World Health Organization (WHO) World Malaria Reports documented a global increase in the number of malaria cases. Despite some countries achieving elimination, malaria increased in both the 10 most highly burdened countries and 11 of the 21 countries earmarked for elimination by 2020 [ 1 ].

A number of daunting realities impact on the potential for substantial further progress. These include: (1) malaria remains a staggeringly large human health problem with 1,200 malaria deaths every day, (2) longitudinal tracking of the effective implementation of existing tools show imperfect outcomes and suggests that existing tools may be insufficient to control malaria in high-transmission settings, no matter how well they are applied, (3) shifts in climate, population growth and movement, and changes in the location and species of vector, threaten to introduce malaria into new settings (for example, greater urban transmission in Africa by Anopheles stephensi ), (4) problems achieving high coverage of current interventions are exacerbated by the emergence of vectors resistant to insecticides, parasites resistant to first-line treatment and parasite strains that evade diagnosis, (5) lessons from the 1970s and our knowledge of parasite biology and ecology tell us that resurgence can be rapid and devastating if public health measures fail or are not maintained, and (6) the COVID-19 pandemic has exposed the vulnerability of global supply chains and the health systems in many malaria endemic settings. Hard won gains can rapidly be lost.

New interventions are needed to reignite the fight against malaria. As for other infectious diseases, vaccines have the potential to impact burden in a cost-effective way and may, in the long term, contribute to the goal of malaria eradication. The feasibility of vaccine-induced protection against malaria has been demonstrated [ 2 ], but the development of malaria vaccines requires the vigorous and sustained engagement of many stakeholders. Recent advances in the understanding of malaria parasite biology, vaccinology and passive immunization approaches, suggest that the next advance in malaria vaccines is within reach─but only with sustained research and development efforts.

The WHO reconvened the Malaria Vaccine Advisory Committee (MALVAC) in 2019, and organized a stakeholder consultation about the state-of-the-art in malaria vaccine development [Vekemans et al. pers. commun.]. MALVAC’s mandate is to provide guidance on research priorities for the development of new malaria vaccines. Detailed WHO perspectives on the medical need and research priorities in malaria vaccine R&D will emerge over the next 12–24 months, but consultations and MALVAC discussions led to the recognition of the need to advance in parallel two distinct strategies:

To support continued engagement to ensure the availability of 1st and 2nd generation vaccine candidates with moderate efficacy, that show potential for widespread use in the next 3–10 years.

To support innovation and stimulate the discovery of next generation, highly protective and long-lasting malaria vaccines; for this to succeed, identifying efficient and cost-effective clinical development, financing and regulatory pathways will be key. Lessons can no doubt be learnt from the accelerated development pathways and approaches being developed for COVID-19 vaccines.

1st Generation Vaccines with partial protection—an important addition to the intervention toolkit

The most advanced malaria vaccine is RTS,S/AS01, developed by Glaxo Smith Kline with support from the Bill and Melinda Gates Foundation, the Walter Reed Army Institute of Research and PATH, and the collaboration of a large number of African and other international research institutions. RTS,S/AS01 targets Plasmodium falciparum sporozoites and demonstrated an efficacy of 39% over 4 years against malaria incidence in Phase III trials in African children aged 5–17 months at the time of dose 1 [ 3 ]. This moderate efficacy, documented in the context of high mosquito net use and similar to the level of protection afforded by well-implemented vector control, is potentially valuable to complement existing strategies for the reduction of malaria disease and death among young children in endemic areas. RTS,S/AS01 pilot implementation is ongoing in three malaria endemic countries—Ghana, Malawi and Kenya [ 4 ]. In addition to consolidating the vaccine’s safety profile, the pilot implementation will generate data on its survival impact and test the feasibility of delivering the four-dose RTS,S/AS01 regimen under routine conditions. Results of the implementation studies are keenly awaited and will be used to guide policy recommendations on the roll out of RTS,S/AS01 in malaria endemic countries.

RTS,S/AS01 has demonstrated the feasibility of developing a malaria vaccine and has laid down a clinical development path for future vaccines. Its use in programmatic contexts will inform our understanding of the potential value of malaria vaccines in combination with other tools for malaria control and elimination.

In addition to RTS,S/AS01, R21/Matrix-M, an RTS,S-like vaccine, is one of several potential second generation vaccines and is currently being tested for efficacy in the field. Notwithstanding enormous technical and practical challenges, the radiation-attenuated sporozoite vaccine, PfSPZ, has undergone extensive testing including in endemic African countries. Although high efficacy has been demonstrated in adults under experimental challenge conditions, efficacy in naturally exposed children is considerably lower, warranting further improvements. Progress is also being made through the evaluation of Rh5, a promising P. falciparum blood stage vaccine candidate, although it will be necessary to achieve higher rates of growth inhibition for such vaccines to yield clinically relevant efficacy.

The evaluation of sexual-stage candidates continues, and new tools to test vaccines designed to interrupt man-to mosquito transmission are being developed. Subunit vaccines that combine multiple antigens from the pre-erythrocytic and blood stages could synergize immune responses and yield higher efficacy. The addition of sexual-stage antigens to these vaccines could potentially enhance their impact on malaria transmission [ 2 ]. Continued investment in the development of these approaches is warranted given the progress to date and the scale of their potential impact on public health. In addition to subunit vaccines, innovations in the development of whole organism attenuated sporozoite vaccines are needed to develop formulations and delivery strategies that facilitate programmatic implementation in endemic countries.

Future malaria vaccines–towards highly efficacious, long-lasting vaccines and a more streamlined development pathway

Malaria vaccines that confer long-term, robust protection, that are inexpensive and relatively simple to deploy, are not on the short-term horizon. To accelerate progress in the development of such vaccines, a deliberate strategic pivot to fundamental discovery science is needed. Breakthrough science, with possibly unconventional approaches, will be required to meet these ambitious goals [ 5 ].

Decoding of the malaria parasite genome together with functional studies using molecular genetic tools, whole genome approaches as well as classical biochemistry and cell biology, are helping unravel the complex biology of the malaria parasite. Advances in understanding how malaria parasites interact with the human host and its immune system should enable new strategies to target the parasite at different stages with novel vaccine approaches. Advances in our understanding of basic human immunology and powerful new tools that enable dissection of immune responses at a systems level need to be brought to bear on malaria. Other advances such as structural vaccinology can provide unique insights into the molecular basis of protective antibody responses that could lead to therapeutic or prophylactic monoclonal antibodies and inform optimization of vaccine antigens to achieve higher efficacy.

The development of vaccines against parasitic diseases is complex and difficult due to the long history of co-evolution of parasites with their hosts. Malaria vaccines are currently envisioned as complementary tools to be added to the core package of interventions. However, the progress made in understanding malaria parasite biology and pathogenesis, as well as both basic and technological advances in human immunology and vaccinology, means the time is right to attempt the development of malaria vaccines with high efficacy. It is time to deepen and expand our ambitions at all levels, basic and translational, to develop future malaria vaccines that are game changers in efforts to eliminate malaria and create a pathway for other parasitic diseases. A highly efficacious malaria vaccine remains an ambitious target, but with commitment of necessary resources, it is more within reach today than ever before.

Availability of data and materials

Not applicable.

Abbreviations

World Health Organization

Malaria Vaccine Advisory Committee

WHO. World Malaria Report, 2019. Geneva, World Health Organization, 2019. https://www.who.int/publications-detail/world-malaria-report-2019

Laurens MB. The promise of a malaria vaccine-are we closer? Annu Rev Microbiol. 2018;72:273–92.

Article   CAS   Google Scholar  

Vandoolaeghe P, Schuerman L. The RTS, S/AS01 malaria vaccine in children 5 to 17 months of age at first vaccination. Exp Rev Vaccines. 2016;15:1481–93.

WHO. The Malaria Vaccine Implementation Programme. 2020 Geneva, World Health Organization, 2020 March. https://www.who.int/immunization/diseases/malaria/malaria_vaccine_implementation_programme/en/

The malERA Refresh Consultative Panel on Basic Science and Enabling Technologies. malERA: An updated research agenda for basic science and enabling technologies in malaria elimination and eradication. PLoS Med 2017;14:e1002451.

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Acknowledgements

Chetan E. Chitnis, Edwin J. Asturias, Philip Bejon, Katharine A. Collins, Brendan S. Crabb, Socrates Herrera, Miriam Laufer, N. Regina Rabinovich, Meta Roestenberg, Adelaide Shearley, Halidou Tinto and Marian Wentworth Members of the Malaria Vaccine WHO Advisory Committee (MALVAC).

The opinions expressed herein are those of the authors and do not necessarily reflect the views and decisions of the World Health Organization.

WHO is supported financially by the Bill and Melinda Gates foundation for malaria vaccine development-related work. The funder played no role in the present manuscript.

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Institut Pasteur, Paris, France

Chetan E. Chitnis

World Health Organization, Geneva, Switzerland

David Schellenberg, Johan Vekemans, Kate O’Brien & Pedro Alonso

University of Colorado School of Medicine and Colorado School of Public Health, Denver, USA

Edwin J. Asturias

KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya

Philip Bejon

Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands

Katharine A. Collins

Burnet Institute, Melbourne, Australia

Brendan S. Crabb

Consorcio Para La Investigacion Cientifica, Cali, Colombia

Socrates Herrera

University of Maryland School of Medicine, Baltimore, USA

Miriam Laufer

IS Global, Barcelona, Spain

N. Regina Rabinovich

Harvard TH Chan School of Public Health, Boston, USA

Leiden University Medical Center, Leiden, The Netherlands

Meta Roestenberg

John Snow Inc, Research & Training Institute, Boston, USA

Adelaide Shearley

Institut de Recherche en Sciences de La Santé, Ouagadougou, Burkina Faso

Halidou Tinto

Management Sciences for Health, Arlington, USA

Marian Wentworth

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Chitnis, C.E., Schellenberg, D., Vekemans, J. et al. Building momentum for malaria vaccine research and development: key considerations. Malar J 19 , 421 (2020). https://doi.org/10.1186/s12936-020-03491-3

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Malaria Journal

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Correlates of malaria vaccine efficacy

Affiliations.

• 1 Institute for Glycomics, Griffith University, Southport, QLD, Australia.
• 2 Department of Medical Microbiology, Radboud University Medical Centre, Nijmegen, The Netherlands.
• 3 Institut für Tropenmedizin, Universitätsklinikum Tübingen, Tübingen, Germany.
• 4 Centre de Recherches Médicales de Lambaréné, Lambaréné, Gabon.
• PMID: 33499692
• DOI: 10.1080/14760584.2021.1882309

Introduction : An effective vaccine against malaria forms a global health priority. Both naturally acquired immunity and sterile protection induced by irradiated sporozoite immunization were described decades ago. Still no vaccine exists that sufficiently protects children in endemic areas. Identifying immunological correlates of vaccine efficacy can inform rational vaccine design and potentially accelerate clinical development. Areas covered : We discuss recent research on immunological correlates of malaria vaccine efficacy, including: insights from state-of-the-art omics platforms and systems vaccinology analyses; functional anti-parasitic assays; pre-immunization predictors of vaccine efficacy; and comparison of correlates of vaccine efficacy against controlled human malaria infections (CHMI) and against naturally acquired infections. Expert Opinion : Effective vaccination may be achievable without necessarily understanding immunological correlates, but the relatively disappointing efficacy of malaria vaccine candidates in target populations is concerning. Hypothesis-generating omics and systems vaccinology analyses, alongside assessment of pre-immunization correlates, have the potential to bring about paradigm-shifts in malaria vaccinology. Functional assays may represent in vivo effector mechanisms, but have scarcely been formally assessed as correlates. Crucially, evidence is still meager that correlates of vaccine efficacy against CHMI correspond with those against naturally acquired infections in target populations. Finally, the diversity of immunological assays and efficacy endpoints across malaria vaccine trials remains a major confounder.

Keywords: Functional assays; Plasmodium falciparum; RTS,S; heterogeneity; immunological correlates of vaccine efficacy; malaria vaccine; pre-vaccination correlates of immunity; systems vaccinology.

Publication types

• Malaria Vaccines / administration & dosage*
• Malaria Vaccines / immunology
• Malaria, Falciparum / immunology
• Malaria, Falciparum / prevention & control*
• Plasmodium falciparum / immunology*
• Sporozoites / immunology
• Vaccination
• Vaccinology / methods
• Malaria Vaccines

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Helminthosis: Immuno-pathology and Anthelmintic Vaccines

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Helminthosis poses a greater global disease burden than malaria and tuberculosis, leading to impaired growth, infertility, and even death in infected individuals. The immuno-pathology of these parasitic infections is intricate, involving a significant expansion of the Th2 lymphocyte subset. Th2 responses, such as IgE production, eosinophilia, and mastocytosis, play crucial roles in both protective immunity and immune-mediated pathology against helminths. The investigation of deep insights into immuno-pathology and host-parasite interactions will offer a strong scientific foundation for conducting pertinent medication development. Research into helminth vaccinology is progressing, demanding a deeper comprehension of vaccine-induced immunity for potent vaccine platforms. Promising approaches including irradiated vaccines, sub-unit vaccines, recombinant proteins with adjuvants, nucleic acid vaccines, and viral vectored vaccines are undergoing preclinical and clinical trials. Progress in understanding helminth immuno-pathology and vaccinology is being propelled by biotechnological advancements in cell culture, molecular biology, and gene editing. 1. This research topic aims to compile original research papers and reviews focusing on histopathological aspects of parasitic disorders, immunopathological investigations of host-parasite immune responses, and host-parasite systems. 2. Emphasis will be placed on understanding the immunological adaptation triggered by parasitic diseases affecting both humans and animals. These diseases result in significant financial losses and have detrimental impacts on the health and welfare of affected hosts. 3. Despite significant advancements in molecular research covering immunology, vaccinomics, and vaccinology, studies in helminthology have been given less priority than bacteriology, virology, and protozoology, such as malaria research. 4. Helminth diseases collectively constitute Neglected Tropical Diseases (NTDs), with a high global burden measured by DALY (disability-adjusted life year) metrics. However, an effective anthelmintic vaccine has yet to be commercialized. 5. Scientists worldwide are striving to comprehend the essential biological activities of helminths and unravel the functions of bio-active molecules (BMAs) crucial for their survival, reproduction, and persistence within or outside hosts. 6. This collection will prioritize exploring molecular insights into parasite-host interactions, antigen presentation, host immune responses, and advancements in vaccine development, including preclinical and clinical trials of promising vaccine candidates. This Research Topic accepts Original Research, Systematic Review, Methods, Review and Mini-Review, Policy and Practice Reviews, Hypothesis & Theory, Clinical Trial, Classification, Technology and Code, Study Protocol, Perspective, Case Report, Conceptual Analysis, Brief Research Report, Data Report, General Commentary, and Opinion. We welcome manuscripts focusing on, but not limited to, the following sub-topics: • Recent progress in pathobiology, immunology and vaccine development for preventing helminth diseases of human and animals. • Cells involved and mechanism of innate recognition of excretory-secretory products (ESP) resulting from helminthosis. • Immune-phenotipization of immune cells (e.g., M1 and M2) participating in the immune response of the animal against helminths. • Cells and cytokines involved in tissue specific host immunity to helminth infection and mechanism how the host accommodate the presence of helminth when they cannot be eliminated. • Novel immunological theories in helminth researches such as roles of ILCs, NETosis, EETosis etc. • Use of novel methods (e.g., CRISPR-Cas, RNAa, RNAi, organoid culture) in the better understanding immunomics and vaccinomics of helminths. • Roles of adjuvants in the polarization of immunity elicited against anthelmintic vaccines. • Micro-RNA based diagnosis of helminth diseases. • Immunological events or explanations of anthelmintic efficacy or resistance. • Insight into the molecular basis of host specificity.

Keywords : Helminthology, Host-parasite interactions, Immunopathological investigations, Anthelmintic vaccines, Disease mechanism, Parasitic Disorders

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Having options can lower vaccine hesitancy, finds research

by Leila Okahata, University of Oregon

Consumers love having choices, even when it comes to vaccines, according to new research from the University of Oregon.

In studies conducted during the height of the pandemic, researchers found Americans are more willing to vaccinate against COVID-19 if they're allowed to choose between multiple vaccine brands rather than being assigned to one. As vaccination rates for preventable, infectious diseases like measles decline in the United States, the findings could help improve public health policy and the way that vaccines are presented.

What psychologists call the "pleasure of choice" may be a simple, though partial, solution to increasing vaccine uptake for many different diseases, said Ellen Peters, director of the Center for Science Communication Research in UO's School of Journalism and Communication. When multiple options exist, people feel empowered if they're given a choice and, as a result, like the option they chose more than if they didn't have the chance to make the decision themselves.

"That's the scenario we faced with COVID-19 vaccines," said Peters, also a professor in psychology. "Whether it's choosing Coke over Pepsi or one outfit over another, there's a pleasure from choosing that causes people to feel more positive about what they get."

Peters and her colleagues conducted two separate online surveys in December 2020 and June 2021 to study Americans' real-time perceptions of the COVID-19 vaccines during their authorization and roll-out. Their findings were published in the Journal of Applied Research in Memory and Cognition .

Unlike with the common flu shot, Americans had the unusual opportunity to decide between different vaccines for COVID-19, said Brittany Shoots-Reinhard, a senior research associate at the Center for Science Communication Research and research assistant professor of psychology at Ohio State University. Multiple pharmaceutical companies were racing to rapidly develop a vaccine, which left room for extensive discussion on the relative merits of the various brands, she said.

To confirm if people were more likely to consider vaccination if given a choice among multiple vaccines, the researchers first surveyed Americans in early December 2020, when the Pfizer COVID-19 vaccine was given emergency-use authorization, with Moderna close behind. They presented all participants with information on both vaccines, including their risks and effectiveness, but half had the option to choose their preferred vaccine while the other half was assigned one.

Of those given a choice, 44% of participants reported being likely or certain to get vaccinated compared to 23% of those told which one they would get.

The pleasure of choice also seems to encourage vaccination among unvaccinated people. The researchers conducted a similar survey in June 2021, after the Johnson & Johnson vaccine was also authorized, to assess vaccine and booster shot perceptions between unvaccinated and vaccinated individuals. Having a choice among Pfizer, Moderna and Johnson & Johnson vaccines increased vaccine and booster intentions in both groups.

"The pleasure of choice is often discussed with consumer products, but it's not really something we think about with health care decision-making," Shoots-Reinhard said. "There hasn't been a lot of research where you get to choose a vaccine and, in this case, simply being offered one of the better vaccines didn't increase vaccine willingness. It really was offering options and allowing choice that gave vaccination intentions a boost."

The pleasure of choice, however, is not a magic bullet to improving vaccine uptake, the researchers warn.

"Highlighting the pleasure of choice is only a partial solution," Peters said. "It's not going to be the only thing needed to convince people to get vaccines. But it did work across our studies with vaccinated and unvaccinated populations. So, when multiple kinds of vaccines exist, providing a choice may make a difference."

Moreover, while choice makes people feel only more positive toward their chosen option, they also feel more negative toward the rejected options. If those options remain viable, however, that should be noted in public health messaging, the researchers said.

"Anytime people are offering choices, it should be emphasized that those rejected options may nonetheless be good options for you later," Peters said. "The pleasure of choice is all yours, but keep in mind these vaccine options will be around for a while and you may prefer a different option down the line. For example, although the single-dose Johnson & Johnson vaccine was less effective than Pfizer and Moderna, it might have been good for someone who didn't have the time to go back for multiple doses later."

To see how vaccine education can be further improved to reduce hesitancy, Peters and Shoots-Reinhard also looked at how to best present vaccine safety and side effects in a 2022 paper. They noticed that current vaccine messaging informs people of the potential side effects but often leaves out how likely they are to occur.

When presenting online survey participants with the numerical likelihoods of experiencing side effects from hypothetical vaccines, 70% of those who got the numbers reported being likely to vaccinate compared to only 54% who didn't get that information.

Although the COVID-19 landscape has greatly changed since 2020 and 2021, and therefore this research cannot be exactly replicated today, the pandemic presented a rare opportunity to study a highly evolving, global health emergency that affected and continues to affect so many people. Vaccines are an important public health tool that go beyond the coronavirus, and the findings are a silver lining in how vaccine efforts in the U.S. can be improved for future epidemics, the researchers said.

"It's about giving people more and better information and allowing them more control over their lives," Peters said. "We want people to get the information they're missing and be able to make their own informed decisions."

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• Published: 13 September 2021

Malaria: a problem to be solved and a time to be bold

• Pedro L. Alonso 1  

Nature Medicine volume  27 ,  pages 1506–1509 ( 2021 ) Cite this article

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Vaccines alone will not be sufficient for the eradication of malaria, which will also require investment in health professionals, better use of data, and universal access to quality health services.

COVID-19 has provided a wake-up call that infectious diseases can have huge health, economic and social costs and require investments that protect the wellbeing of people across the world. By threatening the health and economies of all countries, unprecedented financial efforts and incentives were deployed in a very short period of time to develop and implement new tools against COVID-19, especially vaccines.

This unprecedented investment has revealed the extraordinary power of science, delivering several safe and effective vaccines within months of the sequence of SARS-CoV-2 being determined and shared. The investment and benefits from science, coupled with global solidarity and a focus on equity, should ensure sufficient supply and the equitable distribution of vaccines. It should also be extended to other diseases, such as malaria, that currently threaten the lives of millions of people around the world.

A golden era

History demonstrates that such an investment in malaria can reap remarkable benefits. At the start of the twenty-first century, the transmission of malaria was taking place in 107 countries across five continents, where more than 80% of the world’s population lived 1 . Sub-Saharan Africa carried the brunt of the disease, where a child probably died of malaria every 45 seconds and efforts to control the disease were very limited. Yet this desperate situation had not gone unnoticed.

Towards the end of the last century, there was a growing political and scientific momentum that would lead to a golden era in the fight against this ancient killer of humankind. Insecticide-treated bed nets, artemisinin-based combination therapies, rapid diagnostic tests, new approaches to chemoprevention of target groups with drugs (such as intermittent preventive treatment in pregnancy or in infants, and seasonal malaria chemoprevention) were the extraordinary outputs of a small and underfunded research community.

On the political front, the Abuja Declaration by African Heads of State, followed by the inclusion of malaria in the United Nations Millennium Development Goals, was accompanied by the creation of new funding mechanisms such as The Global Fund to Fight AIDS, Tuberculosis and Malaria, and the US President’s Malaria Initiative 2 , 3 , 4 , 5 . For the first time, substantial financial resources ensured that antimalarial tools could be procured and delivered at scale. The effect has been staggering: 7.6 million deaths and 1.5 billion cases averted in the first 20 years of this century 1 .

These gains have also occurred at a time when many malaria endemic countries have experienced considerable economic growth and social development, both of which are important contributors to decreasing malaria burden. In sub-Saharan Africa, GDP has grown by an average of 4% per annum in the period from 2000 to 2019 6 . During the same time, access to electricity has increased threefold 7 and the percentage of the African population in urban settings has increased from 31% to 41% (ref. 8 ). It is the combined efforts from the scientific community, leadership across the world and socioeconomic development that have contributed to a public health success story and a great return on global health investment.

However, the past five years have shown both the success and the limitations of this effort 1 . More than half (46) of the 87 malaria endemic countries in 2019 are within reach of eliminating the transmission of malaria within their borders. These countries, mostly outside Africa, now account for less than 0.2% of all malaria cases globally, and some, such as El Salvador and China, have recently been certified malaria free 1 , 9 , 10 .

However, for a considerable proportion of the remaining countries with ongoing malaria transmission, reductions in disease incidence and mortality rates have slowed down, particularly in sub-Saharan Africa, where 94% of global malaria cases and deaths occur.

Funding, from both international partners and the endemic countries themselves, has stalled. In the face of a doubling of the population over the past 20 years in sub-Saharan Africa alone, the stark reality is that after US$26 billion of investment to tackle malaria in this region, the estimated number of malaria cases are slightly higher in 2019 (215 million) than in 2000 (204 million) 1 .

The world is therefore likely to continue to see success as a good number of countries become malaria free. However, we are not on track to achieve the agreed targets for reductions in morbidity and mortality by 2030 as set out in the WHO Global Technical Strategy 11 , and malaria eradication is not within sight. In 2017, the WHO raised the alarm on the stalling of progress by declaring that the world was at a crossroads in the fight against malaria 12 , 13 .

Sustaining the gains

First, more financial resources are required. Financing mechanisms and governance also need to acknowledge and enable the leadership of malaria endemic countries, who in turn need to take greater financial responsibility.

Second, plans and activities to control malaria have to be imbedded in the Universal Health Coverage and Primary Health Care agenda 14 , 15 . Robust, resilient, quality health systems are essential to tackle malaria.

Third, data can also support subnational operations, inspired by a problem-solving mindset, to move away from a one-size fits all approach. Countries must invest in quality health-management information systems. The scale up of point-of-care malaria diagnosis, the gradual switch to electronic databases and the investment in malariometric surveys in recent years, which determine the level of malaria in specific locations, have led to increasing availability of reasonable quality data 1 .

Geospatial and mathematical modeling approaches can take into account the inherent heterogeneity of malaria transmission as well as contextual elements, such as access to health facilities, urbanization, important social determinants and other factors. This allows stratification at a national and subnational level, empowering governments to reliably define the optimal mix of malaria interventions that will achieve maximum effect within a given resource envelope.

This sub-nationally tailored approach must extend beyond what is delivered to include local decisions of how to efficiently and equitably deliver to those in need. A sub-national approach will also require further investments in improving surveillance systems, establishment of dynamic integrated national repositories to systematically curate relevant data and national capacity to analyze and make use of the data for locally tailored responses.

Fourth, the malaria community needs to acknowledge the strength and limitations of the tools and strategies available today. We should be able to diagnose and treat all malaria cases. Affordable and easy to use point-of-care diagnostics allow a parasitological confirmatory test. Similarly, safe and highly effective antimalarial medicines exist and can be used to treat all infections. Consequently, no one should be dying of malaria. However, more than 400,000 malaria deaths continue to take place every year owing to a lack of access to prompt quality care.

Preventable deaths

Prevention relies on both tools against the anopheline vector, such as insecticide-treated mosquito nets, and the use of medicines to prevent infections in key target groups. When properly implemented, prevention with medicine results in a substantial reduction in disease and malaria deaths.

However, a lack of prioritization in research and development means that there is a lack of optimal drugs, regimes and formulations for prevention, which represent a barrier to adoption and impact. Furthermore, both drugs and diagnostics will remain challenged by the emergence and spread of drug resistance or parasite gene deletions, a threat towards which the malaria community has so far responded effectively.

In most of sub-Saharan Africa, long-lasting insecticide-treated nets (LLINs) represent the cornerstone of efforts to control the malaria vector. The efficacy of LLINs in the prevention of disease is modest—around 45% in children under the age of five 16 —and the nets need to be replaced every three years. Part of the efficacy of LLINs relies on impregnation with insecticide, against which Anopheline mosquitoes can develop resistance, and they also rely on quality and integrity, which may represent an even greater challenge 17 .

New prevention tools are needed, including against the mosquito vector and antimalarial medicines. Monoclonal antibodies may also provide opportunities to prevent infection for several months during the periods of highest risk for the key target populations.

Various vaccines

COVID-19 reminds us that vaccines remain the most important tool to prevent communicable diseases. The quest for a malaria vaccine started more than a century ago. Today, there is a first-generation malaria vaccine (RTS,S produced by GSK) based on a recombinant protein that targets the circumsporozoite protein, the predominant sporozoite surface protein of Plasmodium falciparum . RTS,S has completed its clinical development and received a positive scientific opinion by the European Medicines Agency 18 . The efficacy of RTS,S is modest — around 40% reduction of disease.

RTS,S is currently undergoing large-scale pilot implementation that involves several hundreds of thousands of children in three African countries, and will be considered for a potential WHO recommendation for broader scale use before the end of the year. If this historic decision is reached, it would represent the first time that a vaccine against a human malaria parasite is recommended for public-heath use and a first vaccine incorporated to the antimalarial armamentarium toolbox, with the potential to avert millions of cases and hundreds of thousands of deaths. More importantly, this first-generation vaccine will show that the 30-year-long development effort has yielded a safe and effective vaccine against a complex parasite.

A limited number of other vaccine candidates are being tested. One of the most advanced is the R21/MM vaccine candidate. This is based on a similar circumsporozoite antigen to RTS,S and has been developed using the Matrix-M adjuvant platform. In a phase 2b trial, R21/MM showed 77% protection over a one-year follow up, among 450 children living in an area of intensely seasonal malaria transmission in Burkina Faso 19 . The results of the phase 2b trial are encouraging, and has increased anticipation for phase 3 trials that, crucially, need to include areas where malaria occurs all year round, as well as long-term follow up to allow adequate comparison with RTS,S.

In recent years, the use of whole parasite immunization strategies has been tried. Whole-cell P. falciparum sporozoite ( Pf SPZ)-based vaccines are a promising way to evoke immunity, as a broad antigenic repertoire of the parasite is present in the pre-erythrocytic development stages, especially in the liver phase. Sporozoites either attenuated by radiation, or with their development arrested via antimalarial medicines, have been reported to induce 100% protection against heterologous challenge in a small number of volunteers 20 .

BioNTech has recently announced its intention to develop a malaria vaccine using its mRNA technology, which has been used so effectively against COVID-19 21 . The goal is to yield a tool that will enable eradication, with a high efficacy in preventing infection and with a long duration of protection. This declaration represents a U-turn in the decades-long trend of major vaccine developers abandoning or scaling down their efforts in the field of malaria. This announcement also represents the potential of new visions and approaches from the field of oncology being applied to address the challenges and complexities of inducing immunity against complex parasites.

Malaria has plagued humans for millennia and has led to an unimaginable loss of life. Malaria has also had an important role in the geopolitics and evolutionary history of humans. The malaria problem is evolving, dynamic and diverse, but it is now concentrated in some of the poorest communities in the world. The lessons of the past two decades show that success in malaria is possible when the world pulls together. However, enormous biological, political, governance, socioeconomic, data and financial challenges remain. These challenges require the world to be bold again.

New tools, including vaccines, could represent game changers, and demand a collective effort that builds on scientific learning and collaboration. But vaccines by themselves will not be a solution to the problem of malaria. No progress will be made without a well-trained and empowered cadre of health workers. Better use of data to plan, implement and track progress, even within a single country, will allow resources to be used more efficiently.

Finally, national decision-making processes must be at the core of public health governance. Governments must identify and serve those communities that are consistently not reached with quality malaria services, especially those delivered through the public health system. Only then can we move again toward global eradication.

World Health Organization. https://www.who.int/publications/i/item/9789240015791 (2020).

World Health Organization. https://apps.who.int/iris/handle/10665/67816 (2000).

United Nations. https://www.un.org/millenniumgoals/ (2015).

The Global Fund. https://www.theglobalfund.org/en/overview/ (2019).

PMI. https://www.pmi.gov/about (2015).

The World Bank. https://data.worldbank.org/indicator/NY.GDP.PCAP.CD (2020).

The World Bank. https://data.worldbank.org/indicator/EG.ELC.ACCS.RU.ZS (2020).

United Nations. https://population.un.org/wpp/ (2019).

PAHO. https://www.paho.org/en/topics/malaria/salvador-first-central-american-country-receive-who-malaria-free-country (2021).

World Health Organization. https://www.who.int/news/item/30-06-2021-from-30-million-cases-to-zero-china-is-certified-malaria-free-by-who (2021).

World Health Organization. https://www.who.int/malaria/areas/global_technical_strategy/en/ (2015).

World Health Organization. https://www.who.int/malaria/publications/world-malaria-report-2017/en/ (2017).

Alonso, P. & Noor, A. M. Lancet 390 , 2532–2534 (2017).

Article   Google Scholar  

World Health Organization. https://www.who.int/teams/primary-health-care/conference/declaration (2018).

United Nations. https://www.un.org/pga/73/event/universal-health-coverage/ (2019).

Lengeler, C. Cochrane Database Syst. Rev. 2 , CD000363 (2004).

Google Scholar  

Lindsay, S. W., Thomas, M. B. & Kleinschmidt, I. Lancet 9 , e1325–e1331 (2016).

World Health Organization. https://www.who.int/immunization/sage/meetings/2015/october/1_Final_malaria_vaccine_background_paper_v2015_09_30.pdf (2015).

Datoo, M. S. et al. Lancet 397 , 1809–1818 (2021).

Article   CAS   Google Scholar  

Mwakingwe-Omari, A. et al. Nature 595 , 289–294 (2021).

Cheney, C. https://www.devex.com/news/plans-for-new-malaria-vaccine-underscore-benefits-of-mrna-beyond-covid-19-100497 (2021).

Download references

Acknowledgements

This manuscript has benefitted from several discussions with partners and colleagues within the Global Malaria Programme, particularly A. Noor, D. Schellenberg and A. Robb.

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Alonso, P.L. Malaria: a problem to be solved and a time to be bold. Nat Med 27 , 1506–1509 (2021). https://doi.org/10.1038/s41591-021-01492-6

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Breakthrough aerosol human infection model gives hope for future tuberculosis vaccine development

University of Oxford researchers have for the first time established a controlled human infection model for tuberculosis (TB) that infects people via the lungs – the way TB enters the body.

The clinical trial, which used the BCG vaccine delivered via aerosol into participants’ lungs, is a first step towards establishing a challenge model that can be used to test new TB vaccines.

Human challenge models have contributed significantly to the development of vaccines for diseases such as malaria or typhoid, especially in early-phase trials. They help scientists select which vaccines should be taken forward into larger field efficacy studies and could be particularly useful with pathogens like tuberculosis, where vaccine development is very difficult.

Unlike malaria and typhoid, where participants were given the virulent form of the disease, it would not be ethical to give people tuberculosis; while there are effective treatments for malaria and typhoid, no such quick, effective treatment exists for tuberculosis and there is no way of knowing for certain that a person has been cured.

The BCG vaccine was used in this trial because it is a live attenuated strain of Mycobacterium bovis – which is related to Mycobacterium tuberculosis , the bacterium which causes tuberculosis in humans – and BCG is known to be safe in humans.

Previous human challenge studies had administered the BCG in the arm, but this method does not mimic the natural route of TB infection into the lungs, which is why the aerosol method was investigated.

The research team recruited healthy people who had never before had the BCG vaccine. They were given BCG by aerosol using a nebuliser into the lungs, and a control group had BCG injected in the arm.

As this was the first time this approach had been used, the researchers gradually increased the dose to ensure it was safe and found the highest dose that did not induce troublesome side effects. They then compared how much BCG could be recovered after administering it in the lungs and through the skin.

The doses of aerosol-inhaled BCG were found to be well tolerated by the participants and there was no significant difference in the frequency of adverse events between the two groups.

Professor Helen McShane, Professor of Vaccinology in the Nuffield Department of Medicine, who led the study, said: ‘When we did lung washes of the participants, we recovered BCG, which is a positive sign in a challenge study. When we eventually test a new vaccine using this method, if we can’t find BCG in the lung washings it would suggest that the vaccine has induced protection. If we hadn’t found BCG in the lung fluid, we would not have been able to move forward with this as a model.’

Professor McShane, who is Director of the NIHR Oxford BRC added: ‘TB is back as the number one killer among infectious diseases. It’s a really difficult pathogen to make a vaccine for, and human challenge models, such as the one we have trialled in this study will undoubtedly play a vital part in helping us to develop a vaccine. For this reason, this is an important first step in establishing that model.’

Earlier this year, Professor McShane launched another study looking at BCG given by aerosol as a vaccine, rather than a challenge agent, and comparing inhalation to vaccination administered through the skin.

The study, whose findings have been published in 'The Lancet Infectious Diseases' , was supported by the Bill and Melinda Gates Foundation and the National Institute for Health and Care Research (NIHR) Oxford Biomedical Research Centre (BRC). 

Link to the published paper: 'The Lancet Infectious Diseases'

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Malaria: The Past and the Present

Jasminka talapko.

1 Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, Crkvena 21, HR-31000 Osijek, Croatia; rh.zmdf@okpalatj (J.T.); rh.zmdf@vecva (A.V.)

Ivana Škrlec

Tamara alebić.

2 Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, Josipa Huttlera 4, HR-31000 Osijek, Croatia; [email protected] (T.A.); moc.liamg@71ikujm (M.J.)

Melita Jukić

3 General Hospital Vukovar, Županijska 35, HR-32000 Vukovar, Croatia

Aleksandar Včev

Malaria is a severe disease caused by parasites of the genus Plasmodium , which is transmitted to humans by a bite of an infected female mosquito of the species Anopheles . Malaria remains the leading cause of mortality around the world, and early diagnosis and fast-acting treatment prevent unwanted outcomes. It is the most common disease in Africa and some countries of Asia, while in the developed world malaria occurs as imported from endemic areas. The sweet sagewort plant was used as early as the second century BC to treat malaria fever in China. Much later, quinine started being used as an antimalaria drug. A global battle against malaria started in 1955, and Croatia declared 1964 to be the year of eradication of malaria. The World Health Organization carries out a malaria control program on a global scale, focusing on local strengthening of primary health care, early diagnosis of the disease, timely treatment, and disease prevention. Globally, the burden of malaria is lower than ten years ago. However, in the last few years, there has been an increase in the number of malaria cases around the world. It is moving towards targets established by the WHO, but that progress has slowed down.

1. Introduction

Malaria affected an estimated 219 million people causing 435,000 deaths in 2017 globally. This burden of morbidity and mortality is a result of more than a century of global effort and research aimed at improving the prevention, diagnosis, and treatment of malaria [ 1 ]. Malaria is the most common disease in Africa and some countries in Asia with the highest number of indigenous cases. The malaria mortality rate globally ranges from 0.3–2.2%, and in cases of severe forms of malaria in regions with tropical climate from 11–30% [ 2 ]. Different studies showed that the prevalence of malaria parasite infection has increased since 2015 [ 3 , 4 ].

The causative agent of malaria is a small protozoon belonging to the group of Plasmodium species, and it consists of several subspecies. Some of the Plasmodium species cause disease in human [ 2 , 5 ]. The genus Plasmodium is an amoeboid intracellular parasite which accumulates malaria pigment (an insoluble metabolite of hemoglobin). Parasites on different vertebrates; some in red blood cells, and some in tissue. Of the 172 of Plasmodium species, five species can infect humans. These are P. malariae , P.falciparum , P.vivax , P.ovale , and P.knowlesi . In South-East Asia, the zoonotic malaria P.knowlesi is recorded. Other species rarely infect humans [ 5 , 6 , 7 , 8 ]. All the mentioned Plasmodium species cause the disease commonly known as malaria (Latin for Malus aer —bad air). Likewise, all species have similar morphology and biology [ 9 ].

The Plasmodium life cycle is very complex and takes place in two phases; sexual and asexual, the vector mosquitoes and the vertebrate hosts. In the vectors, mosquitoes, the sexual phase of the parasite’s life cycle occurs. The asexual phase of the life cycle occurs in humans, the intermediate host for malaria [ 9 , 10 ]. Human malaria is transmitted only by female mosquitoes of the genus Anopheles . The parasite, in the form of sporozoite, after a bite by an infected female mosquito, enters the human blood and after half an hour of blood circulation, enters the hepatocytes [ 11 ]. The first phase of Plasmodium asexual development occurs in the hepatocytes, and then in the erythrocytes. All Plasmodium species lead to the rupture of erythrocytes [ 7 , 9 , 12 , 13 ].

The most common species in the Americas and Europe are P.vivax and P.malariae , while in Africa it is P.falciparum [ 14 ].

2. Discovery of Malaria

It is believed that the history of malaria outbreaks goes back to the beginnings of civilization. It is the most widespread disease due to which many people have lost lives and is even thought to have been the cause of major military defeats, as well as the disappearance of some nations [ 15 ]. The first descriptions of malaria are found in ancient Chinese medical records of 2700 BC, and 1200 years later in the Ebers Papyrus [ 2 ]. The military leader Alexander the Great died from malaria [ 15 ]. The evidence that this disease was present within all layers of society is in the fact that Christopher Columbus, Albrecht Dürer, Cesare Borgia, and George Washington all suffered from it [ 16 , 17 ].

Although the ancient people frequently faced malaria and its symptoms, the fever that would occur in patients was attributed to various supernatural forces and angry divinities. It is, thus, stated that the Assyrian-Babylonian deity Nergal was portrayed as a stylized two-winged insect, as was the Canaan Zebub (‘Beelzebub, in translation: the master of the fly’) [ 17 ]. In the 4th century BC, Hippocrates described this disease in a way that completely rejected its demonic origins and linked it with evaporation from swamps which, when inhaled, caused the disease. That interpretation was maintained until 1880 and Laveran’s discovery of the cause of the disease [ 18 ]. Laveran, a French military surgeon, first observed parasites in the blood of malaria patients, and for that discovery he received the Nobel Prize in 1907 [ 19 ].

Cartwright and Biddis state that malaria is considered to be the most widespread African disease [ 14 ]. The causative agent of malaria is a small protozoon belonging to the group of Plasmodium species, and it consists of several subspecies [ 14 ].

3. The Development of Diagnostic Tests for Proving Malaria through History

Malaria can last for three and up to five years, if left untreated, and depending on the cause, may recrudesce. In P. vivax and ovale infections, the persistence of the merozoites in the blood or hypnozoites in hepatocytes can cause relapse months or years after the initial infection. Additionally, relapse of vivax malaria is common after P. falciparum infection in Southeast Asia. Relapse cases were observed in P. falciparum infections, which can lead to a rapid high parasitemia with subsequent destruction of erythrocytes [ 20 , 21 ]. Children, pregnant women, immunocompromised and splenectomized patients are especially vulnerable to malaria infection, as well as healthy people without prior contact with Plasmodium . A laboratory test for malaria should always confirm clinical findings. The proving of malaria is carried out by direct methods such as evidence of parasites or parts of parasites, and indirect methods that prove the antibodies to the causative agents ( Table 1 ) [ 2 , 5 , 22 ].

Diagnostic tests for proving malaria.

The gold standard method for malaria diagnosis is light microscopy of stained blood films by Giemsa. Due to a lack of proper staining material and trained technicians, this method is not available in many parts of sub-Saharan Africa. The sensitivity of the method depends on the professional expertise, and it is possible to detect an infection with 10–100 parasites/μL of blood. A negative finding in patients with symptoms does not exclude malaria, but smears should be repeated three times in intervals of 12–24 h if the disease is still suspected [ 23 , 24 ]. Diagnosis of malaria using serologic testing has traditionally been done by immunofluorescence antibody testing (IFA). IFA is time-consuming and subjective. It is valuable in epidemiological studies, for screening possible blood donors. It also demands fluorescence microscopy and qualified technicians [ 23 , 25 , 26 ].

Rapid Diagnostic Tests (RDT) for the detection of antigens in the blood are immunochromatographic tests to prove the presence of parasite antigens. No electrical equipment, and no special experience or skills are required to perform these tests. The RDTs are now recommended by WHO as the first choice of test all across the world in all malaria-endemic areas. The sensitivity of the antigen test varies depending on the selected antigens represented in the test. For some RDTs is 50–100 parasites/μL (PfHRP2) to <100 parasites/μL [ 27 , 28 ]. The FDA approved the first RDT test in 2007. It is recommended that the results of all RDT tests should be confirmed by microscopic blood analysis [ 29 ]. It is known that antigens detected with RDT test remain in the blood after antimalarial treatment, but the existence of these antigens varies after treatment. The false-positive rates should be less than 10% [ 30 ]. Several RDT tests in the eight rounds of testing revealed malaria at a low-density parasite (200 parasites/μL), had low false-positive rates and could detect P. falciparum or P. vivax infections or both [ 30 ]. False-positive rates of P. vivax were typically small, between 5% and 15%. On the other hand, the false-positive rates of P. falciparum range from 3–32% [ 30 , 31 ]. Good RDTs might occasionally give false-negative results if the parasite density is low, or if variations in the production of parasite antigen reduce the ability of the RDT to detect the parasite. False negative results of the RDT test for P. falciparum ranged between 1% and 11% [ 31 , 32 , 33 , 34 ]. The overall sensitivity of RDTs is 82% (range 81–99%), and specificity is 89% (range 88–99%) [ 35 ].

Polymerase chain reaction (PCR) is another method in the detection of malaria. This method is more sensitive and more specific than all conventional methods in the detection of malaria. It can detect below one parasite/μL. PCR test confirms the presence of parasitic nucleic acid [ 23 , 36 ]. PCR results are often not available fast enough to be useful in malaria diagnosis in endemic areas. However, this method is most helpful in identifying Plasmodium species after diagnosis by microscopy or RDT test in laboratories that might not have microscopic experts. Additionally, PCR is useful for the monitoring of patients receiving antimalaria treatment [ 36 , 37 ].

Indirect methods are used to demonstrate antibodies to malaria-causing agents. Such methods are used in testing people who have been or might be at risk of malaria, such as blood donors and pregnant women. The method is based on an indirect immunofluorescence assay (IFA) or an ELISA test. The IFA is specific and sensitive but not suitable for a large number of samples, and the results are subjective evaluations. For serological testing, ELISA tests are more commonly used [ 26 ].

Rapid and accurate diagnosis of malaria is an integral part of appropriate treatment for affected person and the prevention of the further spread of the infection in the community.

4. Malaria Treatment through History

Already in the 2nd century BC, a sweet sagewort plant named Qinghai (Latin Artemisia annua ) was used for the treatment of malaria in China [ 38 ]. Much later, in the 16th century, the Spanish invaders in Peru took over the cinchona medication against malaria obtained from the bark of the Cinchona tree (Latin Cinchona succirubra ). From this plant in 1820 the French chemists, Pierre Joseph Pelletie, and Joseph Bienaimé Caventou isolated the active ingredient quinine, which had been used for many years in the chemoprophylaxis and treatment of malaria. In 1970, a group of Chinese scientists led by Dr. Youyou Tu isolated the active substance artemisinin from the plant Artemisia annua , an antimalarial that has proved to be very useful in treating malaria. For that discovery, Youyou Tu received the Nobel Prize for Physiology and Medicine in 2015 [ 39 , 40 , 41 ]. Most of the artemisinin-related drugs used today are prodrugs, which are activated by hydrolysis to the metabolite dihydroartemisinin. Artemisinin drugs exhibit its antimalarial activity by forming the radical via a peroxide linkage [ 42 ]. WHO recommends the use of artemisinin-based combination therapies (ACT) to ensure a high cure rate of P. falciparum malaria and reduce the spread of drug resistance. ACT therapies are used due to high resistance to chloroquine, sulfadoxine-pyrimethamine, and amodiaquine [ 1 ]. Due to the unique structure of artemisinins, there is much space for further research. Extensive efforts are devoted to clarification of drug targets and mechanisms of action, the improvement of pharmacokinetic properties, and identifying a new generation of artemisinins against resistant Plasmodium strains [ 42 ].

The German chemist Othmer Zeidler synthesized dichlorodiphenyltrichloroethane (DDT) in 1874 during his Ph.D. At that time, no uses of DDT was found, and it just became a useless chemical [ 43 ]. The insecticide property of DDT was discovered in 1939 by Paul Müller in Switzerland. DDT began to be used to control malaria at the end of the Second World War [ 40 ]. During the Second World War, the success of DDT quickly led to the introduction of other chlorinated hydrocarbons which were used in large amounts for the control of diseases transmitted by mosquito [ 43 ]. From the late Middle Ages until 1940, when DDT began to be applied, two-thirds of the world’s population had been exposed to malaria, a fact that represented a severe health, demographic, and economic problem [ 29 , 40 , 41 , 44 , 45 ]. DDT is an organochlorine pesticide which was applied in liquid and powder form against the insects. During the Second World War people were sprayed with DDT. After the war, DDT became a powerful way of fighting malaria by attacking the vector [ 43 ].

Five Nobel Prizes associated with malaria were awarded: Youyou Tu in 2015. Ronald Ross received the Nobel Prize in 1902 for the discovery and significance of mosquitoes in the biology of the causative agents in malaria. In 1907, the Nobel was awarded to the already-mentioned Charles Louis Alphonse Laveran for the discovery of the causative agent. Julius Wagner-Jauregg received it in 1927 for the induction of malaria as a pyrotherapy procedure in the treatment of paralytic dementia. In 1947 Paul Müller received it for the synthetic pesticide formula dichlorodiphenyltrichloroethane.

Attempts to produce an effective antimalarial vaccine and its clinical trials are underway. Over the past several decades’ numerous efforts have been made to develop effective and affordable preventive antimalaria vaccines. Numerous clinical trials are completed in the past few years. Nowadays are ongoing clinical trials for the development of next-generation malaria vaccines. The main issue is P. vivax vaccine, whose research requires further investigations to identify novel vaccine candidates [ 46 , 47 , 48 ]. Despite decades of research in vaccine development, an effective antimalaria vaccine has not yet been developed (i.e., with efficacy higher than 50%) [ 49 , 50 , 51 ]. The European Union Clinical Trials Register currently displays 48 clinical trials with a EudraCT protocol for malaria, of which 13 are still ongoing clinical trials [ 52 ]. The malaria parasite is a complex organism with a complex life cycle which can avoid the immune system, making it very difficult to create a vaccine. During the different stages of the Plasmodium life cycle, it undergoes morphological changes and exhibits antigenic variations. Plasmodium proteins are highly polymorphic, and its functions are redundant. Also, the development of malaria disease depends on the Plasmodium species. That way, a combination of different adjuvants type into antigen-specific formulations would achieve a higher efficacy [ 53 , 54 ]. Drugs that underwent clinical trials proved to be mostly ineffective [ 5 , 7 , 55 ]. However, many scientists around the world are working on the development of an effective vaccine [ 56 , 57 , 58 ]. Since other methods of suppressing malaria, including medication, insecticides, and bed nets treated with pesticides, have failed to eradicate the disease, and the search for a vaccine is considered to be one of the most important research projects in public health by World Health Organization (WHO).

The best way to fight malaria is to prevent insect bites. Malaria therapy is administered using antimalarial drugs that have evolved from quinine. According to its primary effect, malarial vaccines are divided into pre-erythrocytic (sporozoite and liver-stage), blood-stage, and transmission-blocking vaccines [ 9 , 54 ]. Most medications used in the treatment are active against parasitic forms in the blood (the type that causes disease) ( Table 2 ) [ 59 ]. The two crucial antimalarial medications currently used are derived from plants whose medical importance has been known for centuries: artemisinin from the plant Qinghao ( Artemisia annua L, China, 4th century) and quinine from Cinchona (South America, 17th century). Side-by-side with artemisinin, quinine is one of the most effective antimalarial drugs available today [ 13 , 39 , 40 ]. Doxycycline is indicated for malaria chemoprophylaxis for travel in endemic areas. It is also used in combination with the quinine or artesunate for malaria treatment when ACT is unavailable or when the treatment of severe malaria with artesunate fails. The disadvantage of doxycycline is that children and pregnant women cannot use it [ 29 ]. Due to the global resistance of P. falciparum to chloroquine, ACTs are recommended for the treatment of malaria, except in the first trimester of pregnancy. ACTs consist of a combination of an artemisinin derivative that fast decreases parasitemia and a partner drug that eliminates remaining parasites over a more extended period. The most common ACTs in use are artemether-lumefantrine, artesunate-amodiaquine, dihydroartemisinin-piperaquine, artesunate-mefloquine, and artesunate with sulfadoxine-pyrimethamine. The ACTs were very efficient against all P. falciparum until recently when numbers of treatment failures raised in parts of Southeast Asia. Atovaquone-proguanil is an option non-artemisinin-based treatment that is helpful for individual cases which have failed therapy with usual ACTs. Although, it is not approved for comprehensive implementation in endemic countries because of the ability for the rapid development of atovaquone resistance. Quinine remains efficient, although it needs a long course of treatment, is poorly tolerated, especially by children, and must be combined with another drug, such as doxycycline or clindamycin. Uncomplicated vivax, malariae, and ovale malaria are handled with chloroquine except in case of chloroquine-resistant P. vivax when an ACT is used [ 7 , 29 , 60 , 61 , 62 ].

Overview of the most commonly used antimalarials.

CNS—central nervous system.

4.1. Malaria in Europe

In Europe, malaria outbreaks occurred in the Roman Empire [ 63 , 64 ] and the 17th century. Up until the 17th century it was treated as any fever that people of the time encountered. The methods applied were not sufficient and included the release of blood, starvation, and body cleansing. As the first effective antimalarial drug, the medicinal bark of the Cinchona tree containing quinine was mentioned and was initially used by the Peruvian population [ 14 ]. It is believed that in the fourth decade of the 17th century it was transferred to Europe through the Spanish Jesuit missionaries who spread the treatment to Europe [ 65 ].

Contemporary knowledge of malaria treatment is the result of the work of a few researchers. Some of researchers are Alphonse Laveran, Ronald Ross, and Giovanni Battista Grassi. In November 1880, Laveran, who worked as a military doctor in Algeria, discovered the causative agents of malaria in the blood of mosquitoes and found that it was a kind of protozoa [ 66 ]. Laveran noticed that protozoa could, just like bacteria, live a parasitic way of life within humans and thus cause disease [ 66 ]. Nearly two decades later, more precisely in 1898, Ronald Ross, a military doctor in India, discovered the transmission of bird malaria in the saliva of infected mosquitos, while the Italian physician Giovanni Battista Grassi proved that malaria was transmitted from mosquitoes to humans, in the same year. He also proved that not all mosquitoes transmit malaria, but only a specific species ( Anopheles ) [ 17 ]. This discovery paved the way for further research.

The global battle against malaria started in 1955, and the program was based on the elimination of mosquitoes using DDT and included malarial areas of the United States, Southern Europe, the Caribbean, South Asia, but only three African countries (South Africa, Zimbabwe, and Swaziland). In 1975, the WHO announced that malaria had been eradicated in Europe and all recorded cases were introduced through migration [ 67 , 68 ].

4.2. Malaria in Croatia

In Croatia, the first written document that testifies to the prevention of malaria is the Statute of the town of Korčula from 1265. In 1874, the Law on Health Care of Croatia and Slavonia established the public health service that was directed towards treating malaria. There was no awareness nor proper medical knowledge about malaria, but the drainage was carried out to bring the ‘healthy air’ in the cities [ 69 , 70 ]. In 1798 physician Giuseppe Arduino notified the Austrian government about malaria in Istria. A government representative Vincenzo Benini accepted a proposed sanitary measure of the drainage of wetlands [ 71 ]. In 1864, the drainage of wetlands around Pula and on the coastal islands began, and since 1902 a program for the suppression of malaria by treatment of patients using quinine has been applied [ 72 ]. In 1922, the Institute for Malaria was founded in Trogir. In 1923, on the island of Krk, a project was started to eradicate malaria by the sanitation of water surfaces and the treatment of the patients with quinine, led by Dr. Otmar Trausmiller [ 66 ]. Since 1924, besides chemical treatment, biological control of mosquitoes has been established by introducing the fish Gambusia holbrooki to Istria and the coast [ 73 ]. In 1930 legislation was passed to enforce village sanitation, which included the construction of water infrastructure and safe wells, contributing to the prevention of malaria. Regular mosquito fogging with arsenic green (copper acetoarsenite) was introduced, and larvicidal disinfection of stagnant water was carried out.

Since malaria occurs near swamps, streams, ravines, and places where mosquitoes live near water, this disease has been present throughout history in Croatia, and it has often become an epidemic [ 74 ]. It was widespread in the area of Dalmatia, the Croatian Littoral region, Istria, and river flows. In the area of the Croatian Littoral, it was widespread on some islands, such as Krk, Rab, and Pag, while the mainland was left mainly clear of it [ 75 ]. The ethnographer Alberto Fortis (1741–1803) who traveled to Dalmatia, noted impressions recording details of malaria that was a problem in the Neretva River valley. Fortis wanted to visit that area, but the sailors on ship were afraid, probably because the were afraid to go to a place where there had been a disease outbreak known as the Neretva plague [ 76 ]. This Neretva plague was, in fact, malaria, and it is believed that due to it, the Neretva was nicknamed “Neretva—damned by God” [ 77 , 78 ]. Speaking of the Neretva region, Fortis states that the number of mosquitoes in that wetland area was so high that people had to sleep in stuffy canopy tents to defend themselves. Fortis also states that there were so many mosquitoes that he was affected by it. During the stay, Fortis met a priest who had a bump on the head claiming it had occurred after a mosquito bite and believed that the fever that infected the people of the Neretva Valley was also a consequence of the insect bites there [ 76 ]. In a manuscript, Dugački described some of the epidemics in Croatia. Thus, noted the small population of Nin in 1348, which was the result of the unhealthy air and high mortality of the population. Three centuries later, in 1646, the fever was mentioned in Novigrad, while the year 1717 was crucial for to the Istrian town of Dvigrad, which was utterly deserted due to malaria. At the beginning of the 20th century, more precisely in 1902, the daily press reported that the Provincial Hospital in Zadar was full of people affected by malaria. The extent to which this illness was widespread is proved by the fact that at the beginning of the 20th century about 180,000 people suffered from it in Dalmatia [ 18 ]. The volume and frequency of epidemics in Dalmatia resulted in the arrival of the Italian malariologist Grassi and the German parasitologist Schaudin. The procedures of quininization began to be applied, and in 1908 25 physicians and 423 pill distributors were to visit the villages and divide pills that had to be taken regularly to the people to eradicate malaria [ 75 ].

Likewise, in Slavonia, malaria had also a noticeable effect, and it was widespread in the 18th century due to a large number of swamps that covered the region. Such areas were extremely devastating for settlers who were more vulnerable to the disease than its domestic population [ 79 ]. Friedrich Wilhelm von Taube (1728–1778) recorded the disease and stated that the immigrant Germans were primarily affected by malaria and that the cities of Osijek and Petrovaradin can be nicknamed "German Cemeteries" [ 80 ]. According to Skenderović, the high mortality of German settlers from malaria was not limited only to the Slavonia region but also to the Danubian regions in which the Germans had settled in the 18th century, with Banat and Bačka [ 79 ] having the most significant number of malaria cases. The perception of Slavonia in the 18th century was not a positive one. Even Taube stated that Slavonia was not in good standing in the Habsburg Monarchy and that the nobility avoided living there. As some of the reasons for this avoidance, Taube mentioned the unhealthy air and the many swamps in the area around in which there was a multitude of insects. Taube noted that mosquitoes appear to be larger than in Germany and that its bite was much more painful. A change in the situation could only be brought about by drying the swamp, in his opinion [ 80 ]. Since malaria had led to the death of a large number of people, the solution had to be found to stop its further spread. Swamp drying was finally accepted by the Habsburg Monarchy and some European countries as a practical solution and, thus, its drainage began during the 18th century, resulting in cultivated fields [ 79 ].

Since epidemics of malaria continued to occur, there is one more significant record of the disease in the Medical Journal of 1877. In it, the physician A. Holzer cites his experiences from Lipik and Daruvar where he had been a spa physician for a long time. Holzer warns of the painful illness noticed at spa visitors suffering from the most in July and August. As a physician, Holzer could not remain indifferent to the fact that he did not see anyone looking healthy. It also pointed out that other parts of Croatia were not an exception. As an example, Holzer noted Virovitica County, where malaria was also widespread. He wanted to prevent the development and spread of the illness. Believing that preventing the toxic substances from rising into the air would stop the disease, the solution was to use charcoal that has the properties of absorbing various gases and, thus, prevents vapor rising from the ground [ 81 ].

Dr. Andrija Štampar (1888–1958) holds a prominent place in preventing the spread of malaria. Štampar founded the Department of Malaria, and numerous antimalaria stations, hygiene institutes, and homes of national health. Dr. Štampar devoted his life to educating the broader population about healthy habits and, thus, prevents the spread of infectious diseases. Many films were shown, including a film entitled ‘Malaria of Trogir’ in Osijek in 1927, with numerous health lectures on malaria [ 82 ]. After the end of the Second World War, a proposal for malaria eradication measures was drafted by Dr. Branko Richter. These measures, thanks to Dr. Andrija Štampar, are being used in many malaria-burdened countries. For the eradication of malaria in Croatia and throughout Yugoslavia, DDT has been used since 1947 [ 83 ].

Malaria is still one of the most infectious diseases that cause far more deaths than all parasitic diseases together. Malaria was eradicated in Europe in 1975. After that year, malaria cases in Europe are linked to travel and immigrants coming from endemic areas. Although the potential for malaria spreading in Europe is very low, especially in its western and northern parts, it is still necessary to raise awareness of this disease and keep public health at a high level in order to prevent the possibility of transmitting the disease to the most vulnerable parts of Europe [ 84 ].

Unofficial data show that malaria disappeared from Croatia in 1958, while the World Health Organization cites 1964 as the year when malaria was officially eradicated in Croatia [ 45 , 75 ]. Nonetheless, some cases of imported malaria have been reported in Croatia since 1964. The imported malaria is evident concerning Croatia’s orientation to maritime affairs, tourism, and business trips. Namely, malaria is introduced to Croatia by foreign and domestic sailors, and in rare cases by tourists, mainly from the countries of Africa and Asia [ 75 , 85 ]. According to the reports of the Croatian Institute of Public Health, since the eradication of this disease 423 malaria cases have been reported, all imported [ 86 ]. Figure 1 shows the number of imported malaria cases in Croatia from 1987–2017, and Figure 2 the causative Plasmodium species of those cases ( Figure 1 and Figure 2 ) [ 86 , 87 ].

Imported malaria cases in Croatia from 1987–2017.

The causative agents of imported malaria in Croatia.

There is also massive and uncontrollable migration from Africa and Asia (mostly due to climate change) of both humans and birds, from countries with confirmed epidemics. This issue is an insurmountable problem if measured by the traditional approach. Insecticides (DDT, malathion, etc.) synthetic pyrethroids, in addition to inefficiency, impact the environment (harm bees, fruits, vines, etc.). Consequently, scientists have patiently established a mosquito control strategy (University of Grenoble, Montpellier) which includes a meticulous solution to the mosquito vector effect (malaria, arbovirus infection, West Nile virus) by changes in agriculture, urbanism, public services hygiene [ 88 ].

Northeastern Slavonia is committed to applying methods that are consistent with such achievements, with varying success, as certain limitations apply to protected natural habitats (Kopački rit) [ 89 ].

There is a historical link between population movement and global public health. Due to its unique geostrategic position, in the past, Croatia has been the first to experience epidemics that came to Europe through land and sea routes from the east. Adriatic ports and international airports are still a potential entry for the import of individual cases of communicable diseases. Over the past few years, sailors, as well as soldiers who worked in countries with endemic malaria, played a significant role in importing malaria into Croatia. Successful malaria eradication has been carried out in Croatia. Despite that in Croatia are still many types of Anopheles , which means that the conditions of transmission of the imported malaria from the endemic areas still exist. The risk of malaria recrudesce is determined by the presence of the vector, but also by the number of infected people in the area. Due to climate change, it is necessary to monitor the vectors and people at risk of malaria. Naturally- and artificially-created catastrophes, such as wars and mass people migration from endemic areas, could favor recrudescing of malaria. Once achieved, eradication would be maintained if the vector capacities are low and prevention measures are implemented. The increased number of malaria cases worldwide, the recrudesce of indigenous malaria cases in the countries where the disease has been eradicated, the existence of mosquitoes that transmit malaria and the number of imported malaria cases in Croatia are alarming facts. Health surveillance, including obligatory and appropriate prophylaxis for travelers to endemic areas, remains a necessary public health care measure pointed at managing malaria in Croatia.

5. Malaria Trends in the World

The WHO report on malaria in 2017 shows that it is difficult to achieve two crucial goals of a Global Technical Strategy for Malaria. These are a reduction in mortality and morbidity by at least 40% by 2020. Since 2010, there has been a significant reduction in the burden of malaria, but analysis suggests a slowdown, and even an increase in the number of cases between 2015 and 2017. Thus, the number of malaria cases in 2017 has risen to 219 million, compared to 214 million cases in 2015 and 239 million cases in 2010. Figure 3 presents the reported number of malaria cases per WHO region from 1990–2017 [ 1 , 90 ]. The most critical step in the global eradication of malaria is to reduce the number of cases in countries with the highest burden (many in Africa). The number of deaths from disease is declining, thus, in 2017 there were 435,000 deaths from malaria globally, compared with 451,000 in 2016, and 607,000 deaths in 2010. Figure 4 presents the number of malaria deaths from 1990-2017 [ 1 , 90 ]. Despite the delay in global progress, there are countries with decreasing malaria cases during 2017. Thus, India in 2017, compared with 2016, recorded a 24% decline of malaria cases. The number of countries reporting less than 10,000 malaria cases is growing, from 37 countries in 2010, to 44 in 2016, and to 46 in 2017. Furthermore, the number of countries with fewer than 100 indigenous malaria cases growing from 15 in 2010, to 26 countries in 2017 [ 1 ].

Reported malaria cases per WHO region from 1990–2017.

Reported malaria deaths per WHO region from 1990–2017.

Funding in malaria has not changed much. During 2017, US$3.1 billion was invested in malaria control and elimination globally. That was 47% of the expected amount by 2020. The USA was the largest single international donor for malaria in 2017 [ 1 , 91 ].

The most common global method of preventing malaria is insecticide-treated bed nets (ITNs). The WHO report on insecticide resistance showed that mosquitoes became resistant to the four most frequently used classes of insecticides (pyrethroids, organochlorines, carbamates, and organophosphates), which are widespread in all malaria-endemic countries [ 1 , 7 , 92 ].

Drug resistance is a severe global problem, but the immediate threat is low, and ACT remains an effective therapy in most malaria-endemic countries [ 1 , 93 ].

According to the WHO, Africa still has the highest burden of malaria cases, with 200 million cases (92%) in 2017, then Southeast Asia (5%), and the Eastern Mediterranean region (2%). The WHO Global Technical Strategy for Malaria by 2020 is the eradication of malaria from at least ten countries that were malaria-endemic in 2015 [ 1 ].

The march towards malaria eradication is uneven. Indigenous cases in Europe, Central Asia, and some countries in Latin America are now sporadic. However, in many sub-Saharan African countries, elimination of malaria is more complicated, and there are indications that progress in this direction has delayed. Elimination of vivax and human knowlesi malaria infections are another challenge [ 7 ].

6. Conclusions

The campaign to eradicate malaria began in the 1950s but failed globally due to problems involving the resistance of mosquitoes to the insecticides used, the resistance of malaria parasites to medication used in the treatment, and administrative issues. Additionally, the first eradication campaigns never included most of Africa, where malaria is the most common. Although the majority of forms of malaria are successfully treated with the existing antimalarials, morbidity and mortality caused by malaria are continually increasing. This issue is the consequence of the ever-increasing development of parasite resistance to drugs, but also the increased mosquito resistance to insecticides, and has become one of the most critical problems in controlling malaria over recent years. Resistance has been reported to all antimalarial drugs. Therefore, research into finding and testing new antimalarials, as well as a potential vaccine, is still ongoing, mainly due to the sudden mass migration of humans (birds, parasite disease vector insects) from areas with a large and diverse infestation.

The process towards eradication in some countries confirms that current tools could be sufficient to eradicate malaria. The spread of insecticide resistance among the vectors and the rising ACT failures indicate that eradication of malaria by existing means might not be enough.

Thus, given the already complicated problem of overseeing and preventing the spread of the disease, it will be necessary to supplement and change the principles, strategic control, and treatment of malaria.

Abbreviations

Author contributions.

Writing the manuscript: J.T., I.Š., and T.A.; updating the text: J.T., I.Š., T.A., and A.V.; literature searches: J.T., I.Š., T.A., and M.J.; tables and figures drawing: I.Š. and M.J.; critical reviewing of the manuscript: A.V.; organization and editing of the manuscript: I.Š. and A.V.

This research received no external funding. The article processing charges (APC) was funded by Faculty of Dental Medicine and Health, Osijek, Croatia.

Conflicts of Interest

The authors declare no conflict of interest.

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David Wallace-Wells

The new age of d.i.y. medicine.

By David Wallace-Wells

Opinion Writer

“Cavities are a communicable disease, and if you’re among the 90 percent of Americans who’s ever had one, you probably got them from your mother.”

So begins “The Rise and Impending Fall of the Dental Cavity,” a remarkably engrossing and, for me, genuinely eye-opening survey of the history and science of tooth decay, published last week by the pseudonymous Cremieux Recueil on his Substack. The bacterium Streptococcus mutans might not seem like the likeliest subject for a 7,600-word general-interest deep-dive, but Cremieux takes detours into the immaculate teeth of dinosaurs, the practice of Neolithic dentistry, the agricultural and industrial revolutions and their effect on our diets, and the dental agony of America’s founding fathers.

His essay is a kind of masterpiece of an emergent form of internet argumentation — one with roots in the blogosphere and the message-board culture of an earlier era but which really flowered in the pandemic years: extremely long, exhaustively researched, often compiled by obsessive nonexperts and aimed at a contrarian lesson about public health, say, or educational achievement, or the origins of the pandemic. For me, the archetypal example is probably the 10-part investigation , with nine “interludes,” into the causes of American obesity published in 2021 by a pair of anonymous researchers, calling themselves Slime Mold Time Mold, who proposed environmental contamination of our water table by the runoff of the mood stabilizer lithium as the driver of the country’s skyrocketing body mass index and have since undertaken the staging of a large-scale, self-supervised “community trial” of what they call the “potato diet.”

In this case, the lesson was about what is going on in the bacteria pools we call “mouths” and what we could do to clean them up. Probably, you remember admonitions from childhood that eating candy will rot your teeth, but that story turns out to be a bit simplistic — the problem isn’t that your teeth hate sugar but that Streptococcus mutans loves it. And when it consumes sugar, the byproduct is lactic acid, which is what really starts to eat away at your dental enamel. Not everyone has an oral microbiome dominated by Streptococcus mutans, but chances are if you do, it was passed to you by your parents, very early on — and if you eat any sugar, you’re very likely to suffer tooth decay.

In places like the United States — where drugs are advertised directly to consumers, pharmacies are lined with whitening toothpaste and yuppie dentists hawk Invisalign between fillings — you might have come to see oral health as primarily a cosmetic matter. (Perhaps, given the costs, even a scam.) But probably a quarter of Americans and more than a third of the world have untreated cavities or tooth decay, and there is an awful lot of science linking oral hygiene with overall health and well-being. The connections are both direct (untreated cavities can host infections, which can spread elsewhere in the body, causing cellulitis and osteomyelitis, among other infections, and other forms of oral bacteria have been linked to colon and colorectal cancers) and indirect (Tooth loss is correlated with higher all-cause mortality, with studies of large-scale tooth loss finding large increases in all-cause mortality risk.) That’s one reason, over the past few decades, there have been periodic efforts to develop a vaccine for tooth decay, focused on Streptococcus mutans.

But “Impending Fall” was not prompted by an F.D.A. approval of such a vaccine, a successful large-scale clinical trial or even news of such a trial getting underway. It wasn’t even occasioned by the publication of new academic research or a new book. Instead, it referred to the rollout of a new product called Lumina, conceived by the startup Lantern Bioworks and sold to customers directly as a probiotic supplement — and an opportunity to participate in something more like a health-care version of a beta-test soft launch.

“Lumina does not have F.D.A. approval, the endorsement of major scientific organizations, or any of the other trappings that sound medicine is supposed to have,” acknowledged Richard Hanania — a prominent anti-woke, pro-vaccine Substack provocateur, whose views on race my colleague Jamelle Bouie called “rancid” and whose furious history of social justice was endorsed by Peter Thiel, Tyler Cowen and Vivek Ramaswamy, among others — reflecting on his decision to “let some genetically engineered bacteria colonize my mouth.” So why had he done this?

He wasn’t motivated by the science or even the reputation of the company’s scientists. “The real reason I brushed my teeth with Lumina,” he writes, “was Scott Alexander told me to.”

Alexander, if you don’t know, is the nom-de-plume of one of the tech world’s most prominent public intellectuals — a Bay Area psychiatrist who used to publish a website of Rationalist musings and investigations called Slate Star Codex and now publishes one called Astral Codex Ten — including, recently, a 15,000-word summary of a 15-hour debate about the origins of the pandemic and a persuasive defense of the utilitarian-philanthropic movement Effective Altruism . Like Hanania, Alexander was supportive of vaccines, and was cautious about Covid, though he has been critical of the F.D.A., which he believes could’ve brought us those vaccines much more quickly. In other words, though his worldview can skew “right,” he is not exactly the conventional liberal stereotype of the anti-science crusader but much closer to its sociological opposite. And in December, he published a long FAQ-style interview with the founder of Lantern Bioworks, which amounted to a kind of endorsement, though Alexander was typically careful not to make claims about Lumina’s efficacy, given that it has not endured conventional clinical trials, and to disclose his own conflicts of interests (his friends at the company and the consulting work his wife did for them).

To a lay reader like me, the idea does indeed appear promising: a $250 one-time treatment to crowd out the bacteria that’s in my mouth now, producing lactic acid anytime I eat sugar, with an engineered variety that will not. (The process is a bit like “gene drive” proposals to outbreed disease-carrying mosquitoes with varieties that can’t harbor malaria or dengue or other diseases menacing to humans.) But it is nevertheless disorienting to find myself, reading about Lumina, in the position to decide, on my own, whether it’s worth it, or safe, to give a novel bacterium a permanent home in my microbiome (“once you use it, it’s in your mouth approximately forever,” Alexander writes). And to thereby undertake what is essentially an unproven and untested treatment without any traditional reassuring oversight. (As Ruxandra Teslo puts it , “most of the direct data comes from small studies in rats and well … most humans are not rats.”)

And yet this position is an increasingly common one, at least in certain corners of the internet, especially since Covid upended an awful lot about not just our lives and our health but also the structure of our epistemic faith. Suddenly, groceries weren’t safe, and then they were; parks weren’t, either, and then they were; masks didn’t work, and then they did, and then maybe they didn’t again. Early on, especially, guidance seemed to shift almost by the week, which emboldened certain people to try to sort it all out for themselves, while others languished in sometimes fearful confusion. In 2020, there were those who placed their pandemic bets on ivermectin and hydroxychloroquine, infamously, but also those hawking vitamin D as a Covid fix and those who didn’t want to wait for the conclusion of clinical trials and instead assembled their own versions of the Covid vaccines, administering them in the form of nasal sprays. The pandemic’s rise of at-home test kits was not just about Covid-19 — which, in fact, became widely available only after many months or regulatory and messaging obstacles — but also about Lyme disease, hormone levels, STIs, menopause, vitamin D, DNA sequencing, thyroid function and many other health indicators. By 2021, a majority of states had passed laws restricting public health authorities from taking actions against future pandemics. In the aftermath of the Covid emergency, the country’s biggest pharmaceutical and perhaps biomedical story has been the spectacular rise of Ozempic, which technically hasn’t even gotten F.D.A. approval for weight loss (though its semaglutide cousin Wegovy has).

Off-label use is nothing new, of course; some estimates suggest up to one-third of all prescriptions for common drugs in the United States may be written for purposes other than those originally intended. And skepticism about the American medical establishment didn’t begin with the pandemic, given decades of hostility toward the authorities like the F.D.A. and an even longer national infatuation with quick fixes, “secret knowledge” and quack cures. But in part because no one was happy with how the pandemic went, and because everyone wanted to believe it would have been easy to handle it better, it did help cultivate what my colleague Michelle Goldberg has called “a coalition of the distrustful” — an anarchic sort of D.I.Y. health and wellness counter-establishment, one that mixes disdain for much conventional wisdom with great faith in the ability of smart people on the internet to do better. “Substackism,” Max Read recently called it, on his own Substack.

“The anti-woke wellness corner of Substack is just one portion of a large and loose network of influencers, podcasters, gurus, scientists, pseudoscientists, quacks, dieticians and scammers,” Read wrote earlier this month. “What links all of these diverse content producers together is less a particular level (or absence) of scientific rigor or expertise (sometimes these guys are absolutely correct!) and more an outsider attitude — a mistrust of institutions.”

To most Americans, not just on the right, this all feels not just familiar but intuitive: that the apparent stumbles of our public health establishment through the past few years would produce distrustful backlash against elite authorities. And there were missteps and mistakes: early on, about testing kits and aerosol spread; in the middle of the pandemic about “natural immunity” and breakthrough infections; and in the post-emergency phase about the universal value of Paxlovid, for instance, which, one recent study suggests, may offer little to no clinical benefit for the fully vaccinated.

But it is also the case that those elites, and that establishment, produced in this same period what is not just the great success of the pandemic but probably the most impressive public-health achievement in a generation: the record-time design, production, clinical testing and delivery of an entirely new kind of vaccine, which, when rolled out less than a year after the country’s first publicly identified Covid case, saved the lives of several million Americans and more than 10 million living abroad.

How should we balance those mistakes and those contributions? Or the pandemic wisdom of the establishment against those who promised that Covid would kill only a few thousand Americans, or who believe the pandemic experience was an unequivocal indictment of the scientific establishment? And how far should we take the argument that the F.D.A. could often move faster?

Not everyone who doubts the wisdom of the F.D.A. is calling for its abolition, of course, and not everyone who’s wondering about the wisdom of seasonal Covid booster shots for the young believes that it would be good if parents seeking shots for their kids were reported to children’s services. Not everyone who was skeptical of those shots at the outset believes they have already killed millions. And not everyone who thinks American schools were closed too long believes those closings were a bigger public policy failure than the Iraq War. But for many the pandemic experience does seem to have been a kind of gateway drug, and it isn’t just among anti-vaxxers that Covid cynicism has given way to a new age of medical libertarianism. In certain corners, it has come to look almost like a second mainstream, at least as sure of itself as the first.