Presently, most of the approaches to target SARS-CoV-2 are directed toward the spike (S) protein. The S-protein plays a crucial role in vaccine development because of its interaction with the immune system.
Almost all the SARS-CoV-2 vaccines currently in clinical development focus solely on the spike protein. While this is a rational target, a single protein may not raise a sufficient or broad enough immune response.
Protection against COVID-19 is largely mediated by an immune response directed against the SARS-CoV-2 S-protein.
The S-protein is responsible for virus-cell binding. Hence it is the target for virus-neutralising antibodies (NAbs). Vaccinologists believe that NAbs induced by vaccination are protective against COVID-19. These NAbs prevent the virus from attaching to the ACE2 receptor on human cells by binding to the S-protein at a few sites, usually in or near the receptor-binding domain (RBD).
The course of a pandemic is usually determined by the transmission pattern of the pathogen. SARS-CoV-2 variants having mutations in the S-protein can have an increased transmission rate. Such mutations can boost the amount of virus shed from an infected person. S-mutations can also increase the virus’ affinity for the ACE2 receptor.
Similarly, alterations can change the shape of the S-protein and impair or even destroy NAb binding sites. Hence vaccine efficacy might be compromised. These “escape mutations” typically arise when the virus is put under selective pressure by antibodies that limit but do not eliminate viral replication. In such conditions, the virus might find a way to escape this pressure and restore its ability to reproduce more efficiently.
Variants have also become less susceptible to neutralising monoclonal antibodies (nMAbs). The N501Y change in the B.1.1.7 variant, for example, is sufficient to almost ablate the activity of several nMAbs, and the South African team’s study shows that almost all of the nMAbs tested against the South African variant N501Y.V2 are ineffective.
According to the preliminary studies conducted by New and Emerging Respiratory Virus Threats Advisory Group (NERVTAG) in the UK, the B.1.1.7 variant, which was initially identified in the south of England in September 2020, carries 17 mutations in its genome, including eight in the spike protein, which forms the basis of the three COVID-19 vaccines that have been licensed in the UK.
The N501Y.V2 (or B.1.351) has many more sequence changes than both the first identified D614G and the B.1.1.7 variants. These sequence changes are located in or close to the RBD. They also affect another NAb target, the N-terminal domain. This variant was associated with a substantial reduction in neutralising antibodies.
Rockefeller University researchers found that the N501Y.V2 sequence changes within the RBD modestly reduce the efficiency with which mRNA vaccine-induced antibodies neutralize test viruses in the laboratory. In addition, a National Institutes of Health study now shows that NAbs induced by the Moderna mRNA vaccine are about 6-fold less active against the N501Y.V2 (B1.351) strain.
Another extremely infectious variant, P.1, has been circulating in Brazil since the middle of 2020. This variant has been implicated in the surge of infections that has struck Manaus, in the Brazilian Amazon, studies show.
But it is not clear whether the reduction in the neutralisation sensitivity of the N501Y.V2 strain to vaccine-induced antibodies is enough to lower the efficacy of a vaccine. Studies are ongoing worldwide to better understand how these different vaccines are affected by the variants.
Realising the S-protein’s high susceptibility to mutations, some vaccine makers have started looking at targets beyond it. The San Francisco-based Vaxart, for example, has included the nucleocapsid (N) protein in its experimental VXA-CoV2-1 oral vaccine. The nucleocapsid is an area “which is historically highly conserved among…coronaviruses”, according to Vaxart.
The idea is even if the S-protein is mutated, the vaccine will still be able to elicit a strong T cell response against N proteins to protect against emerging variants. The orally administered VXA-CoV2-1 was found to activate strong T cell responses against both the S and the N proteins in phase 1 trials. However, the efficacy of the vaccine against variants as they emerge and continue to mutate needs to be confirmed.
Similarly, OSE Immunotherapeutics is focusing on “targets that are not exposed to the body as they are inside the capsid of the virus”. All the first-generation vaccines are targeting the same antigens on the S protein. When a lot of immune responses are generated against the same antigens, it could lead to a pressure selection effect favouring the emergence of variants or mutations, according to the French biotech firm.
Therefore, for its CoVepiT vaccine, OSE uses 11 different targets that are outside these high-mutation regions and are naturally immunogenic in humans. These targets focus on areas of SARS-CoV-2 including S, M, N and non-structural proteins. The basic idea is to confer a non-antibody-based, but a long-term, lymphocyte response to
This approach ensures that even if one of the variants were to mutate to compromise OSE’s S targeting epitopes, “there are still 10 other targets designed to elicit a T lymphocyte response against the pathogen”. OSE is planning to enter phase 1 studies with CoVepiT vaccine.