The coronavirus disease 2019 (COVID-19) vaccines currently in use are mainly based on the production of neutralizing antibodies against the Spike (S) protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). These neutralizing antibodies inhibit infection and reduce disease severity.
However, the emergence of SARS-CoV-2 variants capable of escaping the vaccine-induced immune response has renewed the need for more dynamic vaccines. For example, scientists reported that some vaccines, including ChAdOx, NVX-CoV2373, and Ad26.COV2-S induced lesser protection against the B.1.351 variant analysis in the Phase 3 trials. Additionally, in vitro studies have revealed that wild-type S-specific antibodies induced by the mRNA-1273 and BNT162b1 vaccines showed reduced binding to the B.1.351 variant’s S protein. These findings highlighted that monovalent vaccines solely directed only towards the S protein may not be most efficient in protecting against continually emerging variants.
Owing to these reasons, scientists have renewed their interest in the T cells, which have the potential to offer long-term protection against COVID-19. Although S-specific T cell responses are found in two vaccines; namely, mRNA1273 and BNT162b1, their role in protecting against COVID-19 is not well understood.
Keeping the above drawbacks in mind, scientists strategized to develop a vaccine that could effectively provide immunity against continually emerging SARS-CoV-2 variants. A new study has been published on the medRxiv* preprint server, which focuses on the development of a dual-antigen COVID-19′ T cell’ vaccine. This vaccine is developed based on the expression of both S protein and nucleocapsid (N) protein of SARS-CoV-2, using a next-generation human adenovirus serotype 5 (Ad5) platform.
The current study revealed that for the development of this vaccine, a full-length S protein that includes an SD1 receptor binding domain was used. S1 and S2 domains were modified to enhance surface expression (S-Fusion). Additionally, scientists have used the full-length N protein modified with an Enhanced T cell Stimulation Domain (ETSD) to direct N to the endo-/lysosomal compartment for increased MHC class I and II expression. The hAd5 platform used in this study has omissions in the E1, E2b, and E3 gene regions. These deleted regions cause a reduction in host anti-vector immune responses and, thereby, promote efficient antigen expression. Subsequently, T cell activation occurs in the presence of existing anti-adenovirus immunity. Similar results were obtained from previous clinical studies that had targeted tumor-associated antigens in cancer patients.
Previous studies revealed that SARS-CoV-2 expresses several immunogenic proteins that elicit antibody and/or T cell responses, among which, N protein is the most abundantly expressed and conserved among coronaviruses. Additionally, this protein is utilized as an effective antigen for developing effective therapeutics and vaccines for SARS-CoV. Therefore, considering the previous evidence, researchers of the present study designed a vaccine comprising N-derived antigens to elicit broader protective immunity against SARS-CoV-2. They believe this vaccine will remain effective against SARS-CoV-2 variants.
N protein has several vital roles, for example, virion assembly, viral RNA replication, and release from host cells. Researchers found that almost all COVID-19 recovered individuals developed N-specific antibodies and IFN-g-secreting CD8+ and/or CD4+ T cell responses. Interestingly, scientists found the presence of N-specific CD8+ and/or CD4+ 87 T cell responses in patients who recovered from SARS-CoV in 2003. Researchers revealed that memory T cells also cross-react with N and other proteins of SARS-CoV-2. Individuals with no history of being infected with SARS-CoV, SARS-CoV-2, or Middle Eastern Respiratory Syndrome (MERS) show the presence of cross-reactive SARS-CoV-2 N-specific CD8+ and/or CD4+ T cell responses. This may be due to prior infection with related coronaviruses such as OC43, HKU1, 229E, or NL63. Thereby, scientists pointed out that the development of a vaccine that could stimulate N-specific memory T cell responses could be highly beneficial in protecting against the virus.
The current study reported that the N-ETSD produced higher T cell responses when compared to N without the ETSD. Thereby, the vaccine-expressed antigens can be recalled by T cells, indicating that they can be a potential agent to induce protective immune responses. Further, the T cells were isolated after 14 and 23 days from patients who were inoculated with the newly developed vaccine. The participants belonged to the ongoing Phase 1b clinical trials of the hAd5 S-Fusion + N-ETSD vaccine. Researchers have found activation of T cell responses, by both S and N peptides pools, comparable to the T cells of previously SARS-CoV-2 infected patients.
To further validate the result, the scientists also conducted in silico studies to predict T cell epitope HLA binding. The result revealed a high possibility of this newly developed vaccine being an effective ‘universal’ booster. This is because the hAd5-S-Fusion + N-ETSD 357 vaccine could offer protection against several other viruses that are similar to SARS-CoV-2.
Currently, the hAd5 S-Fusion + N-ETSD COVID-19 T cell vaccine is undergoing clinical trials to understand the most effective vaccine delivery method, i.e., sublingual, intranasal, or oral tablet. The researchers are optimistic about the efficacy of this vaccine against emerging variants.
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.