Safety and efficacy of a third dose of BNT162b2 Covid-19 vaccine
Data from Phase 2-3 of the ongoing pivotal trial of the BNT162b2 vaccine showed that although overall vaccine efficacy was greater than 90% for the period 7 days to 6 months after the second dose, the Efficacy decreased with increasing time after the second dose.9 Additionally, real-world data suggested that the humoral immune response and protection against SARS-CoV-2 infection and non-serious illness appeared to decline in the months following vaccination; these trends were particularly evident in the elderly and in immunocompromised individuals.14.20-22 However, the effectiveness of the BNT162b2 primary vaccination series against severe disease, hospitalization, or death remained high.11,15,21,22
Although data on waning efficacy against infection after the primary two-dose series are still emerging, particularly in the face of emerging variants of SARS-CoV-2 such as variant B.1.1.529 ( omicron),10,14,23 data from the phase 1 study of a third dose of BNT162b2 showed that the geometric mean neutralization titers against the delta variant increased after a booster dose administered approximately 8 months after the second dose.16 Given these data and the immunological and safety results for a booster dose from the pivotal trial, Covid-19 booster vaccinations have been implemented in some countries.24-28 Therefore, it is important that data from prospective randomized clinical trials regarding the safety, immunogenicity and efficacy of booster doses are generated in a timely manner.
In our phase 3 trial, which included more than 10,000 participants, a third dose of 30 μg of BNT162b2 given an average of 10.8 months after the second dose was safe and effective. The safety profile was consistent with results from previous trials, and reactogenicity was similar to that after the second dose.6.9 No new safety signals were identified and no cases of myocarditis or pericarditis were reported.
At a median follow-up of 2.5 months, the relative vaccine efficacy of the third dose of BNT162b2 against Covid-19 was 95.3% (95% CI, 89.5 to 98.3) in participants without evidence of prior SARS-CoV-2 infection. Multiple subgroup analyzes showed that efficacy was generally consistent regardless of age, sex, race, ethnicity, or the presence of coexisting conditions. These efficacy results were observed when the delta variant was the predominant circulating SARS-CoV-2 strain worldwide, although other variants also circulated during the trial (e.g., P.1 [gamma] variant in Brazil).13.29 No cases of severe Covid-19 have been observed in BNT162b2 recipients up to the data collection deadline. Of the protocol-defined Covid-19 cases in the placebo group, none resulted in hospitalization, a finding that supported the durable protection against severe Covid-19 after the two-dose primary series of the BNT162b2 vaccine.
In this trial, prevention of Covid-19 by a third dose of the BNT162b2 vaccine was demonstrated by relative vaccine efficacy of greater than 95% in addition to any residual protection from the two-dose series. Thus, the absolute vaccine efficacy of the third dose compared to a hypothetical unvaccinated population would be even higher. The high efficacy of a third dose of BNT162b2 has significant potential benefits beyond disease reduction, such as preventing sequelae of Covid-19 after breakthrough infections,30 and early data suggest it may be essential for improving efficacy against the omicron variant.23 A third dose may also reduce workplace absenteeism and transmission to those who have not been vaccinated, as suggested by the two-dose primary series.31-33
Actual data on the effectiveness of boosters is limited. However, in a trial involving Israeli adults aged 60 or older, a third dose of BNT162b2 given at least 5 months after the primary two-dose series resulted in an incidence of SARS-CoV-2 infection that was 11 .3 times lower than that in participants who did not receive a booster and an incidence of severe Covid-19 19.5 times lower.24 Also in Israel, an observational study involving participants aged 12 or older and eligible to receive a booster according to Israeli Ministry of Health guidelines showed that the efficacy of a third dose of BNT162b2 given at least 5 months after the second dose was 93% against hospitalization, 92% against severe Covid-19 and 81% against death compared to two doses.34 Another database study from Israel of approximately 850,000 adults aged 50 or older showed that those who received a booster dose of BNT162b2 at least 5 months after the second dose had Covid-19-associated mortality. 90% lower than those who did not receive the extra dose.35 In the United Kingdom, the relative vaccine efficacy of a booster BNT162b2 given at least 140 days after a second dose was 84.4% against symptomatic disease in adults aged 50 years or older, corresponding to a 94.0% absolute vaccine uptake compared to unvaccinated participants.36
Limitations of our current trial include lack of data regarding participants who received a third dose of BNT162b2 after a primary series with a longer interval between doses and regarding long-term protection against SARS-CoV infection. -2. In addition, follow-up of placebo recipients was limited due to unblinding of the trial in some cases to allow for receipt of a third dose of BNT162b2. Longer-term follow-up from this ongoing trial will continue to provide data, as participants will be followed for 1 year to assess the duration of protection after a third dose of BNT162b2. Although we did not assess booster protection after a primary series with different Covid-19 vaccines, early data from a study of heterologous primary booster regimens suggest that BNT162b2 was equally safe and immunogenic when administered after a primary series with the adenoviral vector vaccine ChAdOx1.37 Additionally, US participants accounted for most of the Covid-19 cases in the efficacy assessment. However, the likelihood of vaccine effectiveness differing between countries appears low, even though this trial was not designed for cross-country comparisons. Finally, we did not assess the incidence of asymptomatic infection or assess vaccine efficacy with respect to transmissibility. It is expected that upcoming clinical data on an omicron-based Covid-19 vaccine will clarify whether this new formulation will increase the vaccine’s efficacy against serious diseases, affect transmissibility or improve the duration of protection.
Overall, the data from the C4591031 clinical trial strongly support the administration of a third dose of the BNT162b2 vaccine in persons aged 16 years or older and confirm the increased protection against Covid-19 provided by the primary series.