Immunogenicity, efficacy, and safety of BNT162b2 or mRNA1273 fourth dose

A recent study posted to the medRxiv* preprint server explored the safety, immunogenicity, and vaccine efficacy (VE) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger ribonucleic acid (mRNA) BNT162b2 and mRNA1273 vaccines against its Omicron variant of concern (VOC) in healthcare workers (HCWs) in Israel. 

Following the emergence of SARS-CoV-2 in late November 2019, the coronavirus disease 2019 (COVID-19) pandemic caused widespread illness with varying severity, deaths, and the emergence of several mutated variants. 

The BNT162b2 vaccine rollout began in Israel on December 19, 2020. Further, the Israeli government initiated a BNT162b2 booster vaccination campaign on July 29, 2021, due to the significant waning of vaccine efficacy following the first two doses and the emergence of the fourth wave of the COVID-19 pandemic associated with the Delta VOC. However, the emergence of the heavily mutated SARS-CoV-2 Omicron variant raised concerns regarding the immunity induced by the third vaccine dose due to the high number of breakthrough infections reported and warranted the need to evaluate the effectiveness of the fourth dose of COVID-19 vaccination.

About the study

In the present open-label clinical trial, the researchers assessed the safety and immunogenicity of the fourth dose of two SARS-CoV-2 mRNA vaccines, mRNA1273 and BNT162b2, given four months following a three-dose BNT162b2 regimen. Further, the team evaluated the cumulative incidence of all infections and symptomatic SARS-CoV-2. The researchers then estimated the VE of the fourth dose of both vaccines relative to the previous BNT162b2 three-dose regimen.  

Eligible participants were 18 years or older HCWs vaccinated with three doses of the BNT162b2 vaccine and demonstrated an immunoglobulin G (IgG) antibody titer of 700 binding antibody unit (BAU) or more. Among the 1050 eligible subjects, 120 and 154 were enrolled to receive mRNA1273 and BNT162b2 vaccines, respectively, and were compared to 426 age-matched control groups. Between December 27 and 28, 2021, the participants received the fourth BNT162b2 dose, and between January 5 and 6, 2022, the subjects received the fourth dose of the mRNA1273 vaccine.

Neutralizing and IgG antibody titers, T cell activation, and direct neutralization of live VOCs following the fourth dose vaccination were evaluated among the participants. Additionally, all HCWs were screened for COVID-19 every week during the study period.

Results

The results show that the recipients of the fourth dose of BNT162b2 and mRNA1273 vaccines demonstrated an approximately nine- to 10-times increase in serum SARS-CoV-2-neutralizing and receptor-binding domain (RBD) IgG antibody titers within the second week of vaccination, slightly higher than the initial month following the third dose vaccination.

The T cell responses increased from 50% to 60% in recipients of the fourth dose of the BNT162b2, but the mean number of SARS-CoV-2 S-activated T cells remained the same two weeks after the vaccination compared to before the fourth dose. In the case of those who received the fourth dose of mRNA1273, T cell responses were elevated from 61% to 87%, and the average interferon γ (IFNγ) activated T cells rose from 72±13 to 203±36 two weeks following the fourth dose relative to before vaccination with the fourth dose.

Further, those vaccinated with the fourth dose of BNT162b2 and mRNA1273 vaccines exhibited nearly an eight-times increase in the neutralization of live SARS-CoV-2 Omicron VOC compared to the third dose. However, breakthrough Omicron infections were frequent in the participants following the fourth dose of BNT162b2 and mRNA1273 vaccines, and most were mildly severe yet demonstrated a high viral load.  HCWs vaccinated with the fourth dose of mRNA1273 and BNT162b2 vaccines exhibited an 11% and 30% VE against SARS-CoV-2 infection, respectively.

Approximately 80% and 40% of both vaccine recipients reported local and systemic adverse events, respectively. The adverse events were commonly observed in the younger population compared to the older subjects in both vaccine groups but lacked statistical significance. The local adverse reactions resolved within 1.7 days, whereas systemic adverse reactions resolved within 1.3 ± 2.42 days. The adverse events frequently reported include fatigue, myalgia, and headache. Fever was reported rarely by the vaccine groups and resolved within two days.

Conclusions

The findings showed that the fourth SARS-CoV-2 mRNA vaccine dose restored the neutralizing and IgG antibody titers to peaks similar to titers induced by the third dose. The study indicated that the fourth vaccine dose did not lead to significant adverse reactions apart from mild and quickly resolving local and systemic adverse events. Thus, it suggests the safety profile of the fourth vaccine dose is comparable to the previous vaccine doses.

Overall, the findings indicate that the fourth dose of the mRNA1273 and BNT162b2 COVID-19 vaccines did not enhance the immunity but produced peak levels similar to previous vaccinations. Hence, it urges the need for developing next-generation vaccines in the light of breakthrough asymptomatic and mild Omicron infections with high infectivity potential to curb the ongoing COVID-19 pandemic. Additionally, continued monitoring of these vaccines is required to understand their longevity and population exhibiting the highest immunity.

*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.

Written by

Shanet Susan Alex

Shanet Susan Alex, a medical writer, based in Kerala, India, is a Doctor of Pharmacy graduate from Kerala University of Health Sciences. Her academic background is in clinical pharmacy and research, and she is passionate about medical writing. Shanet has published papers in the International Journal of Medical Science and Current Research (IJMSCR), the International Journal of Pharmacy (IJP), and the International Journal of Medical Science and Applied Research (IJMSAR). Apart from work, she enjoys listening to music and watching movies.