Erwan Sallard 1,2
[email protected]
1 Institute for Virology and Microbiology, ZBAF, Witten/Herdecke University
2 Biorisk section, Effisciences (https://www.effisciences.org/)
TL;DR
Vaccines have a major scope: infectious diseases are still one of the main causes of death worldwide, and the threat of future pandemics and rising resistance to antibiotics means their burden on society will likely increase. Vaccines are arguably the most powerful tool to counter infectious diseases and still have a lot of room for improvement in terms of efficiency and number of pathogens that can be combatted.
Vaccines are relatively neglected: the field is smaller and receives less investment than many other domains of biology and medicine despite higher scope. In particular, certain specific research and engineering questions within vaccinology appear unduly neglected compared to their expected returns (see a tentative list of such topics below).
Actions to bring the field forward are tractable. Not only biologists and medical professionals can get involved, but also engineers, administrators and IT professionals, and there are options to fund impactful work on vaccines.
Report
In the coming decades, mankind is going to face the severe (potentially even existential) health threats of probable emerging pandemics, whether natural or man-made, as well as the already ongoing rise of antimicrobial resistance. In addition, infectious diseases still represent a major cause of mortality, especially in the tropics, with probably 20-25% of world deaths [1]. Vaccination is one of the most powerful tools to combat each of these threats, and therefore in my opinion one of the highest impact fields for biological research and industry. In this essay, I intend to provide a rational assessment of the impact of research in vaccinology and related domains, as well as examples of topics where people from different areas of expertise may contribute the most to medical progress.
For context, I am a last year PhD student working on adenovirus vector biotechnology. This essay is the result of my reflexions on EA oriented biological research, my PhD work, readings and writings [2] on the antimicrobial resistance (AMR) crisis, exchanges with experts and participation to the ISV vaccine congress. I will mainly focus on academic research because that’s what I know best, but I will also try to give advice for careers in industry and policy-making although that will be less detailed. This report is destined in particular to students aligned with EA values: I hope this report will help them get the information necessary to choose their studies and career paths.
Although the concept of vaccine dates back more than two centuries, clinically approved vaccines are available against only around 30 human pathogens out of hundreds [3]. Furthermore, the evolution of existing pathogens and the emergence of new ones constantly threatens to annihilate the progress already achieved. Fortunately, the recent surge of new technologies (lipid nanoparticles, viral vectors, designer protein subunits...) and the rapid improvement of the understanding of immunology is leading to the establishment of numerous more efficient ways to train our immune system and the vaccinology R&D field is poised to qualitatively expand. Recent successes, including the mRNA COVID vaccines and the WHO recommendation of two vaccines against the still deadly malaria disease [4] may be followed by dozens of others, and significantly decrease the worldwide burden of infectious diseases, if well-targeted research efforts are conducted and industry and governments are willing to follow.
Why you may not want to work in vaccinology:
- I prefer to work on other answers to the antimicrobial resistance crisis
Many pathogenic bacteria are evolving resistance against antibiotics, the current gold standard of treatment. They already kill more than one million people per year and this number may grow tenfold within one generation because the improvement of antibiotics doesn’t keep up with the propagation of resistance. Potential solutions to the AMR crisis would thus have an extremely high positive impact [5], and both human and veterinary vaccines may play an important role toward this goal. However, other options are under investigation, including new classes of antibiotics [6], phage therapy, lysins and improved protection and diagnostic equipment.
In 2018, the company Acahogen had its new antibiotic plazomicin approved by the FDA, but ran bankrupt a few months later because profits could not match the huge expense undertaken in clinical trials. This example shows that fighting scientific discoveries won’t have a significant impact against AMR unless the medical, industry and government fields are ready to test and deploy new solutions at the required scale. Although progress has been made, AMR is still very neglected compared to its present and future scope and a lot of effort in communication and politics is required to raise public mobilisation and create economic environment that can sustain the deployment of innovative therapies.
2. I prefer to work on biorisk management and policy
Future pandemics may be the result of human malevolence or negligence. Although vaccines help to decrease the risk that emerging diseases represent, other approaches may be equally or more impactful, such as regulating research and preparing countermeasures to avoid careless manipulations to cause damage, or developing equipments and protocols so that research and medicine can keep working even in destabilized societies. Since societal collapse and existentially threatening pandemics are impossible to predict and somewhat unlikely, this area appears high-risk high-reward in terms of impact, in opposition to the more secure and short-termist vaccine field.
3. Most of the research in vaccines is relatively inefficient
As in most professional areas, a lot of players in vaccinology do not perform well and economic incentives are not always aligned with real long-term societal needs. This means that the really high-performing teams may be hard to find and offer a limited number of positions.
Since vaccinology is clinic-oriented and clinical trials often last a decade and cost hundreds of millions of dollars, it has long been limited by the slow-moving, risk-averse big pharmaceutical companies. Recent public investments to de-risk the field are accelerating developments and the various epidemics of the last two decades have taught the different actors of the field to cooperate efficiently, which means that it is now much easier to fund impactful vaccine R&D and there are straightforward highways to bring promising products to the clinic. Nevertheless, certain areas remain neglected by the big companies driving the field, especially concerning innovative technologies that still need a lot of time to bear fruits.
On the other hand, a relatively large part of the vaccine community focuses on very fundamental questions that may never find concrete applications. Furthermore, successful vaccine development requires the cooperation of many different domains (immunology, pharmacology, microbiology, manufacture...) already at an early stage, but because of the difficulty to coordinate efficiently researchers or teams with very different skillsets, these subfields remain in some instances compartmentalized. Another dividing factor is the separation between academia, startups and big pharmaceutical companies, which operate under different constraints and often pursue conflicting goals. However, as mentioned before the integration and interconnectedness of vaccinology is progressing as indicated by the fast-increasing number of collaborations, the improving transparency of pharmaceutical companies and the recent public large-scale coordination and support structures for vaccine R&D such as operation warp speed and CEPI (see below).
Relatively neglected research axes with high potential:
- Mucosal vaccines
Most currently used vaccines are administered in muscles, leading to suboptimal protection at the actual site of infection for most pathogens (respiratory tract, intestine, etc.). Indeed, these mucosa have a specific immune system that is not entirely connected with systemic immunity. Although the awareness for the need of mucosal vaccines is rising, solutions are still rare. Currently, the main limitations of mucosal vaccines are first, the difficulty for vaccine components to cross the mucosa physical and chemical barriers that separate the organism from its environment and microbiota; and second, peripheral tolerance, a process through which the immune system does not fight antigens found in mucosa [7]. Although peripheral tolerance helps the body not to overreact against microbiota and food, it is to be avoided for efficient mucosal vaccination. Research on these particular areas is warranted.
In addition, the mucosal immunity and its reaction to vaccines is still quite poorly understood, and fundamental research on this topic would probably help solve the current issues of mucosal vaccines, in particular by establishing animal models relevant for human applications and identifying correlates of protection.
Given that each mucosa represents a different environment, vaccines suited for one administration route (e.g. pill for sublingual delivery) may not be optimal to protect other mucosa (e.g. sexually transmitted pathogens). However, the buccal mucosa is sufficiently connected with several other organs [7] for pill-formulated vaccines to represent a priority target, with the additional advantage of easily upscalable and low-cost needle-free administration, and thinner mucus easier to cross by vaccine components.
2. Outer membrane vesicles (OMVs)
This type of vaccine, still experimental, is produced from membranes of gram-negative bacteria that express and present the desired vaccine antigens. Advantages of this technology include low cost and easy production even in low and middle income countries (LMIC) and high immunogenicity due to the display of bacterial proteins and sugars, making adjuvants unnecessary and further decreasing vaccine costs [8]. OMVs appear in particular to be very promising in the fight against AMR. Currently, the main limitations of OMVs are heterogeneity of vaccine batches and difficulties to upscale.
3. Universal vaccines
Although very efficient against the original pandemic coronavirus strains, COVID vaccines only offer a limited protection against new variants. This narrowness of protection is shared by numerous other vaccines, for example it’s the reason why flu vaccines are modified each year to account for the evolution of influenza viruses. Moreover, current vaccines would not protect against an emerging pathogen distantly related to the microbe they have been designed for.
The aim of universal vaccines is to protect against an entire family of pathogens. They would not only better combat immune-evading variants than more restricted vaccines, but could also in theory prevent pandemics emergence if made available for a broad range of pathogen families that have a high risk of causing pandemics.
The research on universal vaccines focused so far on coronaviruses and influenza. The leading approach consists in choosing protein fragments of the very well-known SARS-CoV-2 spike protein coming from different variants, based on informatic modeling of the complementarity of antibodies that these variants induced in patients. Finally, all the fragments are fused together in order to train the immune system of vaccinated people to recognize them all [9]. Although heavily reliant on clinical data and pathogen-specific datasets in this example, universal vaccines may soon be extended to other pathogen families. Moderna announced their goal to develop universal vaccines for each major virus family until 2030. This seems excessively ambitious, but even if they establish only one such vaccine this would already be a major success.
4. Vaccines for neglected tropical diseases (NTD)
“Neglected tropical diseases” designates a diverse set of infectious diseases prevalent in LMIC (malaria, tuberculosis, trypanosomiasis, schistosomiasis, ascariasis...) which all combined still kill more than 2 million people per year and handicap many more. As their name indicates, the medical and economic investments against these conditions are very low compared to their heavy burden on world health [10]. The situation is slowly improving, once again largely thanks to the efforts of CEPI, Gates fundation and the Wellcome trust, but R&D of vaccines against NTDs remains deficient and largely limited to academia.
5. Vaccine manufacturing
The COVID pandemics showed how difficult it is to produce and distribute high-quality, low-cost vaccines to the entire world quickly. Although vaccine design was completed only a few weeks after the publication of the SARS-CoV-2 genome in January 2020, it took more than one and a half years to vaccinate most of the population of the richest countries, and in many LMIC vaccine coverage remains incomplete to this day. As the expected deadlines to distribute vaccines after the start of the pandemics are becoming tighter, manufacturing needs to be accelerated without losing in quality; and as numerous innovative new types of vaccines are designed, the manufacture constraints need to be dealt with already at early stages. Furthermore, needle-injected vaccines present significant inconvenients because they rebuke many people and the need for health professionals to administer them slows deployment down, so other delivery methods such as pills, micropatches and nasal sprays may improve vaccine usage and acceptance [11,12]. Manufacturing requires the coordination of different specialities, from basic biologists to pharmacologists and engineers.
6. Vaccine vector mechanistic immunology
The final effects of vaccines on the immune system (above all IgG secretion and T cell responses) are well understood, but the complex biological processes that lead to vaccine administration to these final responses are in many instances poorly characterized. Having a detailed idea of which vaccine components induce which biological pathway would help to predict in advance which changes can be applied to improve vaccines. This topic of fundamental research will require the establishment and thorough study of animal models representative of vaccine behavior in humans, or the extensive collection and curation of clinical data from the early stages following vaccination. Example of concrete projects in this area include understanding the role of M cells of different mucosal compartments in immunisation and how vaccines could utilize them [13].
7. mRNA vaccines... but not like everyone else does
There is a massive hype around mRNA vaccines, with good reasons, but this means that the field is currently crowded. To have an impact, individual researchers should look at original ways to apply and improve mRNA vaccines. Such approaches include using polymeric carriers instead of lipid nanoparticles to transport the mRNA, in order to decrease production costs and side effects and more easily customize vaccine properties [14]. Self-amplifying RNA vaccines represent another “marginal” topic: the mRNA they use encodes not only the antigen to vaccinate against, but also a replicase which multiplies the mRNA copies in vaccinated cells, with the goal of decreasing vaccine dose and side effects while increasing antigen immunogenicity [15]. Here, a primary goal would be to shorten and optimise the replicase.
8. Adenovirus capsid engineering
Although mRNA vaccines have monopolised the spotlight during the COVID pandemics, adenovirus-based vaccines played an equal role in combatting the pandemics [16]. This impressive track record combined with their transitory fall out of fashion suggests that bringing new people into working on them would have a substantial impact. These vectors could be used to solve many of the problems listed above [17,18]. Until now, adenovirus vaccine development mainly focused on customizing gene expression and incorporating new transgenes, while no modifications of the capsid (the proteins at the surface of the adenovirus, that are the main vaccine component to interact with the immune system and thus determine vaccine efficiency) have been tested for vaccines until 2022 [19]. The fledgling research topic of vaccine vector capsid engineering could therefore be the new frontier that will bring about major vaccine improvements.
Other areas where motivated and skilled workforce can make a difference:
- Gene drives
Many pathogens of both humans, farm animals and crops are transmitted by insects. Gene drives consist in genetically modifying wild insect populations to make them collapse or become incapable of transmitting the disease, thanks to genetic constructs (usually based on CRISPR-Cas9) that can be transmitted to all the progeny of GMO insects instead of just half of it as is the case for natural inheritance. This facilitates the propagation of the sterilizing or resistance-providing gene to whole insect populations starting from a limited number of insects modified in laboratory [20]. Gene drives are already quite famous in the EA community thanks to the works of Kevin Esvelt and hold a huge potential, but are unpopular with many voters and politicians due to fears (to some extent justified) of misuse and lack of control on this technology. It is therefore not clear how much of this potential will have even a chance to turn concrete. However, very promising news have recently been published about less controversial versions of gene drives, where mosquitoes were infected with Wolbachia bacteria so that they lose the ability to transmit dengue. Real world trials in Indonesia, Colombia and Brazil resulted in 77-97% decreases in dengue incidence sustained over several years [21,22].
2. Entomology
Since so many diseases are transmitted by insects, studying them is key to understand how to improve human health, but this discipline is relatively unpopular among biology students while there is an increasingly dire shortage of medical entomologists [23,24].
3. Gene therapy
Gene therapy has been a more innovative area than vaccinology, despite having in itself a much lower scope due to the rarity of targeted diseases. Many of the technologies recently adopted in vaccinology were invented in a gene therapy context, for example the mRNA and adenovirus vector vaccines that have been at the forefront of the fight against the COVID pandemics.
4. Clinical trials regulations and public health policy
Without massive public sector investments and preparation in advance of fast-track priority clinical trial protocols, it could have taken a decade instead of a year until COVID vaccines were approved by regulatory agencies. This illustrates that governments have a critical role to play in accelerating vaccine innovation and development, and especially that adapted incentives and clinical trials protocols can be adapted to any health threat to decrease clinical trials costs and duration without sacrificing anything in safety [25]. In order to adapt to the specificities of new treatments that keep being developed and to solve the limitations identified during the COVID pandemics, there is still a lot of work to do in this area, not only on vaccines but also with other priority treatments, for example those contributing to the fight against AMR.
5. CEPI, Wellcome trust and Gates fundation
Let’s keep focused on administration and policy careers. The coalition for epidemic preparedness innovations (CEPI) is a consortium aiming at advising national agencies and coordinating international support, and at funding for research on vaccines for emerging diseases. One of its main activities is the “100 days initiative” whose aim is to decrease the time between epidemic start and vaccine approval to just 100 days (compared to almost one year in the case of COVID). This approach involves among others prior validation of quickly adaptable vaccine platforms (such as mRNA or adenovirus vaccines where only the antigen needs to be changed when a new pathogen is discovered and manufacture is already established), drilling of action plans and maintenance of alertness state, modelisation to try and predict which vaccine designs have the best chances of protecting against potential future pathogens, and building facility networks to enable scientists to quickly access all the materials and expertise they need when designing and testing new treatments in the face of an emerging epidemic. CEPI is also advocating for human challenge trials, in which volunteers would be infected with the pathogen following vaccination in order to know very early if candidate vaccines are efficient and to gather data on how to improve them if needed.
Likewise, the Wellcome trust and Gates fundation are major funders of medical developments (vaccine and others) trying to maximise positive impact and therefore often financing research in areas neglected by big pharmaceutical companies due to lack of expected economic returns.
6. Applying AI to vaccine development and deployment
In January 2020, the SARS-CoV-2 genome was sequenced and published on the internet with largely automated processes, following which it took only a few days before numerous candidate vaccines had been designed using well-known methods. We are not that far from completely automatizing the whole process from pathogen discovery to vaccine design, production and manufacture at scale in biofactories, and automatization could help further shorten the deployment timetable.
Furthermore, better prediction tools could help forecast pathogens immune escape mutations and prepare countermeasures, or find out how to best modify vaccine components, or even decide how to prioritize clinical trials based on intermediary results in order to respond faster to current or future pandemics. Data-driven approaches are already to a large extent able to design proteins that best activate immune responses, thanks to huge datasets already generated in in vitro and clinical studies and curated; however, more experimental data would have to be generated before models can be trained on numerous other questions, for example how vaccine vector surface modifications would modify transduction levels, antigen expression and immunogenicity.
7. Veterinary medicine
The current fashionable word in WHO and other health agencies is “one health”: human health partly depends on the health of animals that we rely on for farming and more and that can transmit us new pathogens. The current avian flu epizooty, which is frequently crossing species barriers including toward wild mammals in South America in 2023, may end up causing human outbreaks, highlighting the need for poultry universal flu vaccines [26].
In addition, veterinary treatments can be tested faster and at lower cost than human treatments due to less strict safety rules and the possibility to challenge vaccinated animals with the pathogen to know fast and with only a small number of animals if the treatment is efficient. Veterinary medicine thus offers an avenue for the testing of innovative vaccine technology and provides pharmaceutical companies with quick economic profits that can help fund human clinical trials, thus making them less risk-averse.
Conclusion
I hope this report helped you to get a better understanding of the current biomedicine research field or to identify the topics where you can best contribute given your personal preferences and skillset. To learn more on this subject, you may have a look at the references below or even register at a dedicated course, for example one of the vaccine network courses: www.icavt.org.
Finally, several promising vaccine initiatives can be funded by private individuals, for example through the CEPI fund. The most impactful charity to donate to is probably GAVI (https://www.gavi.org/donate), a consortium funding the delivery of vaccines to poor and isolated regions where they are most needed. Active since 2000, it is estimated that GAVI already saved at least 9 million lives [27].
References
[1] https://ourworldindata.org/causes-of-death mortality of infectious diseases is indicated to be 14%, but this was data from before COVID-19 and several of the diseases registered as “noncommunicable” are triggered or worsened by pathogens (hepatitis viruses for cirrhosis, papillomavirus for cancer, rhinovirus for asthma...) so at least 2 or 3 million deaths can be added to the current burden of infectious diseases.
[2] https://legrandcontinent.eu/fr/2023/04/26/10-points-sur-lantibioresistance/
[3] https://www.who.int/teams/immunization-vaccines-and-biologicals/diseases
[4] https://www.who.int/news/item/02-10-2023-who-recommends-r21-matrix-m-vaccine-for-malaria-prevention-in-updated-advice-on-immunization
[5] https://forum.effectivealtruism.org/posts/W93Pt7xch7eyrkZ7f/cause-area-report-antimicrobial-resistance
[6] Shukla et al., bioRxiv, 2023. https://www.biorxiv.org/content/10.1101/2023.05.15.540765v1
[7] Tsai et al., Expert review of vaccines, 2023. https://doi.org/10.1080/14760584.2023.2268724
[8] Zhu et al., Vaccines, 2021. https://doi.org/10.1128/mbio.01707-21
[9] Cohen et al., Science, 2022. https://www.science.org/doi/full/10.1126/science.abq0839
[10] Svitlana Kondovych, Life Chemicals, 2021
[11] https://news.mit.edu/2023/vaccine-printer-could-help-vaccines-reach-more-people-0424
[12] Braun et al., Cur Op in Immu, 2023. https://doi.org/10.1016/j.coi.2023.102374
[13] Islam et al., Biomaterials, 2019. https://doi.org/10.1016/j.biomaterials.2018.10.041
[14] Yang et al., Advanced Healthcare Materials, 2023. https://doi.org/10.1002/adhm.202202688
[15] Pourcel et al., Drug Discovery Today, 2022. https://doi.org/10.1016/j.drudis.2022.103341
[16] Watson et al., Lancet Infect Dis, 23rd June 2022.
[17] Afkhami et al., Molecular Therapy - Meth. & Clin. Dev., 2016. http://doi.org/10.1038/mtm.2016.30
[18] Coughlan et al., Molecular Therapy, 2022. https://doi.org/10.1016/j.ymthe.2022.01.034.
[19] Dicks et al., Molecular Therapy, 2022. https://doi.org/10.1016/j.ymthe.2022.08.002
[20] Bier, Nature Reviews Genetics, 2022. https://www.nature.com/articles/s41576-021-00386-0
[21] Utarini et al., N Engl J Med, 2021. https://pubmed.ncbi.nlm.nih.gov/34107180/
[22] Lenharo et al., Nature, 2023. https://doi.org/10.1038/d41586-023-03346-2
[23] https://time.com/5144257/fewer-scientists-studying-insects-entomology/
[24] https://onlineentomology.ifas.ufl.edu/about/entomology-articles/why-the-world-needs-medical-entomologists-more-than-ever/
[25] https://forum.effectivealtruism.org/posts/mZK974Whp6cPoyqLM/the-relative-ethicalness-of-clinical-trial-designs
[26] Guyonnet & Peters, Gates Open Res, 2020. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578560/
[27] Jaupart et al, BMJ global health, 2019. http://dx.doi.org/10.1136/bmjgh-2019-001789
This is great, Erwan! Thanks for sharing this.