By Dr. Tomislav Meštrović, MD, Ph.D.

A new study published on the preprint server medRxiv* by a research group from the U.S. and Germany indicates that a novel BNT162b1 RNA-based vaccine against coronavirus disease (COVID-19) induces functional and proinflammatory T cell responses in almost all participants – marking another landmark achievement for this promising vaccine candidate.

The extensive and rapid spread of COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), prompted urgent and conscientious research to develop a vaccine, which is (according to many experts) our only hope of returning to normalcy.

We recently reported that a research group from the U.S. and Germany showed a robust neutralizing antibody response and a promising safety profile of the BNT162b1 RNA-based vaccine against COVID-19.

However, some cases of asymptomatic virus exposure have been linked to cellular immune response without seroconversion, indicating that SARS-CoV-2-specific T cells may be relevant in disease control – even in the absence of neutralizing antibodies.

This study by the same research group now complements the previous report with novel data, providing a detailed characterization of antibody and T cell immune responses elicited by BNT162b1 vaccination.

A non-randomized open-label phase 1/2 trial
In a nutshell, the messenger RNA (mRNA) vaccine technology allows delivering precise genetic information encoding a viral antigen together with an intrinsic adjuvant effect to antigen-presenting cells. Preclinical models against multiple viral targets have proven the effectiveness of this approach.

Moreover, fast and highly scalable mRNA manufacturing and lipid-nanoparticle formulation processes allow speedy production of many vaccine doses, which makes it amenable for rapid vaccine development and adequate pandemic vaccine supply.

This study is a second, non-randomized open-label phase 1/2 trial in healthy men and non-pregnant women, aged between 18 to 55 years of age. Most participants were Caucasian, with one Asian and one African American participant.

Concentrations of IgG antibodies and SARS-CoV-2 neutralizing titers were assessed at baseline, 7, and 21 days after the priming dose, and 7 and 21 days after the boosting dose. Additionally, CD4+ and CD8+ T cell responses were characterized prior to priming vaccination and 7 days after boost vaccination.

Highly coordinated immune response
“We observed concurrent production of neutralizing antibodies, activation of virus-specific CD4+ and CD8+ T cells, and robust release of immune-modulatory cytokines such as interferon-gamma, which represents a coordinated immune response to counter a viral intrusion”, say study authors.

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A majority of study participants had Th1-skewed T cell immune response (which supports cell-mediated immunity) with pronounced CD8+ and CD4+T cell expansion. Interferon-gamma was produced by a high fraction of CD8+ and CD4+ T cells specific for the receptor-binding domain (RBD) of the spike glycoprotein of SARS-CoV-2.

Basically all vaccinated volunteers mounted RBD-specific T cell responses detected with specific assays, which was performed without prior expansion of T cells. Albeit the strength of the T-cell responses varied significantly between participants, the researchers observed no clear dose-dependency of the T cell response strength.

Confirming the dose-dependency and neutralization responses
“The study confirms the dose-dependency of RBD-binding IgG and neutralization responses and reproduces our previous findings for the 10 and 30 µg dose levels of BNT162b1 in the U.S. trial”, further state study authors.

A noteworthy observation is that two shots of BNT162b1 at a dose level as low as 1 µg were capable of inducing RBD-binding IgG levels higher than those observed in convalescent sera.

Furthermore, two BNT162b1 doses of 1 to 50 µg induced robust CD4+ and CD8+ 32 T cell and strong antibody response, with RBD binding IgG concentrations clearly exceeding those in a COVID-19 convalescent human serum panel.

A protective potential against COVID-19
“The robust RBD-specific antibody, T-cell and favorable cytokine responses induced by the BNT162b1 mRNA vaccine suggest multiple beneficial mechanisms with the potential to protect against COVID-19”, study authors summarize their main findings.

However, this study is not without limitations. First of all, the sample size is rather small and restricted to participants below 55 years of age. Furthermore, deconvolution of epitope diversity, the characterization of HLA restriction, and the persistence of potentially protective immune responses over time have not been studied.

Nonetheless, the results are quite promising and indicate that stimulation and robust expansion of T cells might be achieved at the lowest mRNA-encoded immunogen levels. Now, we all eagerly await follow-up studies and novel findings while the race for the vaccine continues.

*Important Notice
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.

Source:
Meštrović T. (2020). Pfizer/BioNTech COVID-19 vaccine shows promise – virus neutralizing antibodies achieved. News Medical. Available at: https://www.news-medical.net/news/20200702/PfizerBioNTech-COVID-19-vaccine-shows-promise-virus-neutralizing-antibodies-achieved.aspx
Journal reference:
Sahin, U. et al. (2020). Concurrent human antibody and TH1 type T-cell responses elicited by a COVID-19 RNA vaccine. medRxiv. https://doi.org/10.1101/2020.07.17.20140533.