Evolving vaccine discovery and development pathways for emerging pathogens

Emerging pathogens are global public health threats and pose unique challenges for vaccine development. Specifically, how do we prepare for the unknown and can we do it quickly enough? Most vaccines for emerging infectious diseases (EIDs) have required over a decade for development. While there is a risk that the next emerging pathogen could be one we are unaware can cause human disease, the viruses that pose the most pressing threat for emergence and sustained transmission in humans are often not entirely unknown but related evolutionarily and antigenically to known human pathogens. Reflecting on several of the latest viral pathogens to emerge or reemerge, this has been the case for Zika, Ebola, pandemic influenza, SARS-Cov-1 and -2, and, more recently, m-pox. Thus, while the precise circumstances of spillover into humans and conditions allowing subsequent sustained human-to-human transmission have been difficult to predict, we have a good idea of key families of human pathogens and routes of transmission (e.g. respiratory, vector-borne) that are high risk. For example, there was a strong understanding following the SARS-CoV-1 outbreak, prior to the COVID-19 pandemic, that similar respiratory viral pathogens could subsequently emerge with potentially devastating global consequences. The COVID-19 pandemic also illustrated the importance of building a pipeline of basic science and technology (which underpinned the ability to quickly roll-out mRNA vaccines) and pathogen-specific mechanistic understanding that can be quickly applied to vaccine development. Ideally, these technologies should be re-useable, with adaptation to emerging pathogens. Learning from the COVID-19 pandemic and other recent virus outbreak public health emergences, we propose the following ideas for thinking beyond conventional approaches for vaccine development for EIDs.

Current vaccines are selected for clinical development mostly based on the antibody titers elicited by vaccination, as well as short-term protection against infection: Most studies test for vaccine efficacy in animals at one-month post-vaccination. Longer intervals between vaccination and challenge infection are desirable but impractical to implement during pandemic emergencies. Consequently, such discovery approaches are contrary to our expectation of durable protection from vaccination. During naturally receding immunity or in some cases, owing to sub-optimal plasma cell durability, antibody titers wane with time after vaccination.¹ Moreover, IgM antibodies can remain for weeks and months after vaccination even as class-switching and ramping up of IgG antibodies occurs during this period. The pentavalent structure of IgM antibodies may afford better protection than IgG antibodies for certain pathogens, despite the same antigen specificity.² Consequently, the potency of IgG-mediated humoral immunity to protect humans against infectious agents may be overestimated by conventional vaccine discovery approaches. Furthermore, such vaccine discovery approaches ignore the multi-layered nature of adaptive immunity. Indeed, mRNA vaccine-induced protection against symptomatic SARS-CoV-2 infection was reliant on virus spike-specific T cells; neutralizing antibody titers associated with protection against symptomatic SARS-CoV-2 could only be attained after vaccination and infection, or hybrid immunity.³ A singular focus on serological responses to select vaccine candidates for clinical development could thus prove disappointing in clinical trials or real-world vaccine effectiveness studies. Inclusion of other adaptive immune parameters, such as memory B and T cells, could safeguard against such disappointment, especially since vaccine-induced memory T cells are the first to respond to breakthrough infection.⁴ Development of simple T cell assays that do not require isolation of peripheral blood mononuclear cells, such as that for SARS-CoV-2 specific T cells, are much needed to make assessment of cellular immunity widely accessible. A more holistic measure of the adaptive immune response, beyond relying on just neutralizing antibody titers, should thus be adopted to support decision making in pandemic vaccine development.

We also have increasing understanding of the mechanisms through which innate immune responses during an initial exposure to a pathogen or vaccine can shape the efficacy of long-term immune protection. Innate immune responses are well known for their broad, non-specific protection over a limited period. However, signaling from innate immune cells is also important to drive the conversion of memory cells to pathogen-specific protective phenotypes and influences the durability of those responses. We think about examples informed by our research and others, including the potential of early innate lymphocyte activation to regulate the production of polarized T cell responses and antibody sub-classes⁵ or the importance of localized mucosal immune activation to induce IgA production.⁶ With respect to antibody durability, vaccines that trigger innate immune activation via pathogen replication, such as yellow fever and measles vaccines, are associated with long-term protection.⁷ These concepts suggest that testing the capacity of vaccine candidates to induce innate immune activation consistent with the pathogen's life cycle or adaptive immune polarization typical of pathogen-specific protection (e.g. T helper (Th)1/Th2/Th17-cell responses or antibody sub-class production) will be key to identify the most promising vaccine candidates. Defining the innate immune responses that are critical for adaptive immunity from vaccination would also form the foundation to discover and develop new adjuvants; adjuvants are needed to trigger innate immune responses that cannot be elicited by certain non-replicating vaccines. Although some of these measures are considered during early-stage vaccine development, these additional immune read-outs beyond seroconversion are not routinely retained as benchmarks throughout the vaccine development process in humans.

Beyond improving our benchmarks for defining vaccine success and efficacy, there is a need to develop technologies to protect against antigenically diverse viral variants with respect to both T and B cell epitopes. For EIDs, it is difficult to select the prototype strains of high-risk pathogens that should serve as the basis for vaccine development. Even in the ongoing COVID-19 pandemic, the ability to generate neutralizing antibodies against diverse new variants is a limitation of current vaccines, necessitating more frequent boosters and vaccine reformulations. This has primarily been addressed by updating vaccine antigenic components for the new circulating variant or seasonal strains, similar to seasonal updates to influenza virus vaccines. Yet, there is also the potential of rational antigen design to drive cross-protective T cells and antibodies or to use adjuvants to diversify adaptive immune responses.⁸ This might have the effect of casting a wider net for the antigenic diversity of pathogens at high risk for emergence. While broadly neutralizing antibodies towards evolutionarily diverse groups of viruses can often be identified, it has remained a challenge to elicit antibody responses towards these unique specificities during vaccination. Efforts to design immunogens that drive cross-protective responses to HIV and its variants,⁹ or for “universal” protection against influenza virus are underway and the potential of cross-protective T cells to compensate for the evolutionary pressures of neutralizing antibodies on viral immune evasion is being investigated.¹⁰ Investment in developing such new technologies and resources to generate broadly cross-protective immunity against families of diverse and evolutionarily divergent viruses should be supported not only for these high burden human pathogens but also with respect to virus families at high-risk for emergence.

In the face of emerging viral pathogens, we recognize the challenges in predicting the next outbreak or pandemic. However, recent advances highlight the opportunities to evolve our vaccine and adjuvant design and discovery pathways, and harness the malleable and multifunctional nature of our immune system to protect the world from emerging pathogens.

Declaration of interests

ALS is an inventor on an international patent application, PCT/SG2023/050610, Title: Novel vaccine composition with improved protection efficacy. EEO has served in various advisory capacities on dengue and COVID-19 to Sanofi Pasteur, Takeda, MSD, Johnson and Johnson as well as Novartis. He also holds a patent on a rapid approach to developing live attenuated viral vaccines (US Patent Serial No. 17/249,329, Title: Rapid method of generating live attenuated vaccines).