SARS-CoV-2 Vaccine Development: Immunological Considerations and Perspectives

As we move ever closer to that ultimate triumph of science over nature – a successful vaccine for COVID-19 – it is increasingly important that we, and especially those in the business of vaccine development, harbor an understanding of how the biology of SARS-CoV-2 interacts with our own, and how we may leverage that interaction to create the most effective vaccine possible. In an article published last month in Nature Reviews Immunology, Jeyanathan et al. outline some of the most important considerations for vaccine development, including the nature of the host immune response, existing clinical evidence for cross-reactivity with previous human coronaviruses, and how the nature of different vaccine modalities may fair in producing the most effective and far-reaching immunity.

The first aspect the authors consider is that of innate immune responses to COVID-19. Just as MERS-CoV and SARS-CoV were able to suppress – to a degree – innate immune responses upon infection, so too has SARS-CoV-2 demonstrated a capacity to diminish dendritic and T cell responses from early on (Zhou et al., 2020; Remy et al., 2020). Because of the body’s inability to mount a productive immune response early in infection, the authors posit that severe COVID-19 is associated with high viral titer and a dysregulated immune response that may do more harm than good. For these reasons, the authors claim that the vaccine must be a strong activator of innate immune responses.

Immune protection against SARS-CoV-2 infection, like immune protection against nearly all viruses, relies heavily upon both antibody and T cell activation and proliferation. Indeed, a study by Grifoni et al. showed that 100% of individuals in their cohort who had recovered from COVID-19 had CD4+ T cells specific for S protein, and 70% had CD8+ T cells specific for the S protein (Grifoni et al., 2020). In addition, these individuals had high levels of both neutralizing antibodies and T cells, especially in the respiratory tract. This fact necessitates the development of respiratory mucosal vaccines which – compared to parenteral, injected vaccines – induce stronger respiratory memory T cell responses (Turner et al., 2014). In the original SARS pandemic, mild and moderate disease cases were associated with Th1-type responses, while severe lung sequelae were associated with the induction of Th2-type immune responses (Oh et al., 2012). Thus, the authors conclude, the COVID-19 vaccine should induce memory cells with a Th1 phenotype.

Upwards of 60% of individuals who have not previously been exposed to SARS-CoV-2 exhibit CD4+ T cells that are reactive to at least one SARS-CoV-2 structural protein, indicating cross-reactivity of these T cells between the novel coronavirus and one of the other four known human coronaviruses – 229E, NL63, OC43, and HKU1 (Grifoni et al., 2020; Braun et al., 2020). (These individuals did not have confirmed exposures to any of the human coronaviruses, but the authors inferred exposure from the presence of cross-reactive lymphocytes.) These cross-reacting T cells have a strong affinity for the S2 subunit of the SARS-CoV-2 spike protein. Vaccines that utilize the S2 subunit as an antigen may therefore elicit more wide-spread immunity, for SARS-CoV-2 and other, possibly undiscovered, coronaviruses. 

As previously discussed, parenteral injected vaccines – though adept at inducing trafficking of IgG to respiratory mucosa – do little to induce IgA responses or memory T cell activation at these sites. Therefore, respiratory mucosal vaccinations are necessary for sufficient priming of the immune system to challenge by SARS-CoV-2. One major issue with the respiratory route of vaccination, however, is presented by the use of potentially unsafe adjuvants and the necessity of repeated delivery that characterize the ubiquitous inactivated virus or protein subunit vaccines. Recombinant viral-vector vaccines present a potential solution, as they do not require adjuvants or multiple boosters. Recombinant vaccines which utilize the human serotype 5 adenovirus (Ad5) or the chimpanzee-derived adenovirus (ChAd) present the safest and most efficacious options for vaccine development at this time.

So much goes into the development of vaccines that are protective and, more importantly, safe. The information summarized here and provided by the work of Jayanathan et al. and others represents a good guide for those seeking to be informed about their choice of vaccine, and with over 160 vaccine candidates in clinical trials as of last month, there will surely be many opportunities for consumers to weigh their options. It is important to keep in mind that any vaccine that becomes available to the public will have met FDA standards of approval and will be monitored long term for safety. For those seeking a more in-depth look at the theory behind vaccine development, or perhaps for clinicians looking for guidance on the best vaccine for a patient, this article by Jayanathan et al. and others like it are a good place to start.