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Pre-clinical development

In vivo studies to characterize B- and T-cell responses

Pre-clinical in vivo studies were performed in order to characterize vaccine-elicited B cell and T cell responses in animal models. These studies included the assessment of activity and proliferation of B cells and T cells, including neutralizing antibodies, cytokine responses, and evaluation of protection from infection challenge after prime-boost vaccination.[1] By infecting the animal model, in this case a non-human primate, with the SARS-CoV-2 virus following vaccination, this models transmissibility – the ability to spread the virus to others.[1] The animal models utilized in these studies included both mice and non-human primates, which more adequately test vaccines for their potential efficacy and tolerability in humans in comparison to mice.[1][2]

Adaptive immune responses to COVID-19 mRNA vaccine (BNT162b2) in pre-clinical in vivo studies in BALB/c mice.[1]

  • Vaccination was shown to be highly immunogenic in a BALB/c murine model, as a single dose of vaccine elicited high neutralizing antibody titers and induced B cell homing[1]
  • Serum IgG against the vaccine antigen developed within 7 days of vaccination, in a dose-dependent manner.[1]The relevance of these findings is supported by initial studies in humans investigating the adaptive immune responses to SARS-CoV-2, which demonstrate that B-cell immunity to natural infection with the virus is primarily detected against S and N proteins[3]
  • Vaccination also elicited strong CD8+ and TH1- and TfH-type CD4+ T cell responses, and also significantly expanded circulating CD4+ and CD8+ T cells in these animal studies.[1] Of note, both CD4 and CD8 T-cell immune responses, as well as a favorable TH1 cytokine profile, have been reported in humans post-SARS-CoV-2 infection, and associations between the breadth of the T-cell immune response and the severity of illness (i.e., the higher the number of T-cells circulating, the less severe the illness experienced) have been shown[3]

Adaptive immune responses to COVID-19 mRNA vaccine (BNT162b2) in pre-clinical in vivo studies in rhesus macaques[1]

  • Vaccination was shown to be highly immunogenic in a rhesus macaque non-human primate model, as a single dose of vaccine elicited S1 (spike protein subunit)-binding IgG and serum pVNT50 (pseudovirus 50% neutralization titers), with levels for both increasing further with a second dose[1]
  • Vaccination also elicited strong antigen-specific CD4+ and CD8+ T-cell responses with a TH1-biased immune profile[1]
  • Vaccinated rhesus macaques and age-matched placebo controls were challenged with SARS-CoV-2 55 days after their second vaccination:[1]
    • Viral RNA was detected in bronchoalveolar lavage (BAL) fluid on Days 3 and 6 post-challenge from placebo-controlled animals1; however, no viral RNA was detected in BAL fluid from vaccinated macaques at any time-point tested[1]
    • Nasal and oropharyngeal (OP) swabs were also collected from vaccinated rhesus macaques and age-matched placebo controls post-challenge.[1] Viral RNA was detected at all time-points tested post-challenge from nasal swabs from placebo control animals[1]; however, viral RNA was detected on Day 1 only from nasal swabs from vaccinated macaques.[1] Similarly, viral RNA was detected on Days 1 and 3 post-challenge from OP swabs from all placebo control animals, but viral RNA was detected from OP swabs from only 3 vaccinated animals (of 6) on Day 3 and 2 vaccinated animals (of 6) on Day 61[1]
    • These data demonstrate strong evidence for potential prophylactic prevention against robust and systemic infection with SARS-CoV-2 after vaccination with the COVID-19 mRNA vaccine BNT162b2, as the viral challenge model shows a statistically significant limited expression of viral RNA in multiple respiratory tract secretions in vaccinated animals as compared with controls animals[1]

Limitations to pre-clinical in vivo studies include:

  • Animal models differ from human models and these studies form a precursor for studies in healthy volunteers to assess reactogenicity and immunogenicity[1]
  • Animal data regarding antibody titers cannot be extrapolated to humans as there is currently not a human sera standard to which these data may be compared[1]
  • In addition to this, correlates of immune protection against SARS-CoV-2 in humans are not yet fully understood, therefore, the immunogenicity profiles in the animal models in these studies may be limited in their application to humans[1]
  • Finally, the non-human primate model is an infection challenge model, not a COVID-19 disease model, thus these studies are limited in their application to human disease[1]

Overall, these studies demonstrate that this vaccine is highly immunogenic in murine and non-human primate animal models, capable of eliciting a strong antiviral immunity profile in both models, including high neutralizing antibody titers, TH1-biased cytokines, and strong CD8+ and CD4+ T cell responses. In addition, viral challenge of vaccinated animals in the non-human primate model demonstrated limitation and clearance of viral infection, as compared to placebo controls. These findings strongly supported the use of this vaccine for clinical testing as a COVID-19 vaccine candidate in Phase 1/2 clinical trials.[1]

References

  1. Vogel A, et al. Nature. 2021. DOI: 10.1038/s41586-021-03275-y.
  2. Rivera-Hernandez T, et al. Discov Med. 2014;18(101):313-322.
  3. Poland GA, et al. Lancet. 2020;S0140-6736(20)32137–1.

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