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BNT162b2 vaccine effectiveness against SARS-CoV-2 omicron BA.4 and BA.5

SARS-CoV-2 omicron (B.1.1.529) subvariants BA.4 and BA.5 were first detected in South Africa in December, 2021. Their spike (S) proteins are identical (hereafter referred to collectively as BA.4/5) and include L452R and F486V mutations in the receptor binding domain, which might lead to increased immune evasion or the ability to infect host cells, or both. Evidence also suggests that COVID-19 vaccine responses are less effective at neutralising BA.4/5 than BA.1 or BA.2 subvariants of omicron. Subsequently, BA.4/5 have become the predominant subvariants in the USA and globally. To our knowledge, no studies evaluating the effectiveness of COVID-19 vaccines against BA.4/5 have been published to date. Using the same test-negative design approach as in our previous analyses, we determined the effectiveness of BNT162b2 (Pfizer–BioNTech) against BA.4/5 among members of the health insurance provider Kaiser Permanente, based in Southern California, CA, USA aged 18 years or older, who were diagnosed with an acute respiratory infection and tested for SARS-CoV-2 Published Online November 7, 2022 https://doi.org/10.1016/ S1473-3099(22)00736-8 Authors’ reply We thank Udit Singhal and colleagues for their Correspondence regarding our Article. They raise crucial questions regarding our statistical considerations during study planning. We agree that the non-inferiority limit should not exceed the effect size of the active treatment; however, during study planning, the effect of antibiotic prophylaxis was unknown because almost all previous studies had been done with antibiotic prophylaxis. Only two retrospective studies from 1984 and 1986 were available when planning our study in 2018. The confidence intervals in those studies were wide and indicated that rates of sepsis might be 8–13% higher or 3–16% lower without antibiotic prophylaxis than with antibiotic prophylaxis. Consequently, they were underpowered to give any conclusion on the effect of antibiotic prophylaxis. In the absence of reliable data, we believe that transrectal biopsies, the most commonly used biopsy method in this field, were relevant to consider in the planning of our study. By choosing a 4% limit, we could compare sepsis rates between the study populations and compare results to the most commonly used biopsy method applied worldwide. However, the lower non-inferiority limits proposed by Singhal and colleagues would require the inclusion of several thousand patients, which is practically impossible for most centres. Singhal and colleagues also claim that use of χ2 statistics for sample size estimation was inappropriate and that the recommended test is the Farrington-Manning test. We were unfamiliar with the FarringtonManning test, but acknowledge it is an alternative. However, our position remains that χ2 statistics are used widely and are appropriate for assessing dichotomous outcomes in two independent populations. The idea of post-hoc sample size estimation and power analyses is fundamentally flawed and it is highly inappropriate to do such analyses when interpreting observed results. The power of observed effects is evident from the width of the confidence intervals or the size of the p values. We found a difference in sepsis rates of 0·0% (95% CI –1·37 to 1·37), and we find it peculiar that Singhal and colleagues did not make any comments on these results. The width of our 95% CIs indicate that the study was adequately powered and that it is unlikely that the true sepsis rate is higher then 1·37%, making the 4% limit and any post-hoc power analyses irrelevant. Whether clinicians are willing to accept a possible 1·37% higher sepsis rate when performing transperineal biopsies without antibiotic prophylaxis versus with an antibiotic prophylaxis is another question and is open for debate. Finally, Singhal and colleagues asked whether it is always necessary to conduct an adequately powered trial to change clinical practice. Because current guidelines and most clinicians continue to recommend and use antibiotic prophylaxis despite knowledge obtained from single-arm studies, the obvious answer is yes. The narrow width of the confidence intervals in our randomised controlled trial show that the study is adequately powered, and we believe the study provides new information that adds valuable evidence to current knowledge and, hopefully, tips the balance in favour of omitting routine antibiotic prophylaxis. Omitting routine antibiotic prophylaxis was also encouraged in a recent editorial citing our study, showing that at least some believe the question is no longer unanswered.

We thank Udit Singhal and colleagues for their Correspondence regarding our Article. 1 They raise crucial questions regarding our statistical considerations during study planning.
We agree that the non-inferiority limit should not exceed the effect size of the active treatment; however, during study planning, the effect of antibiotic prophylaxis was unknown because almost all previous studies had been done with antibiotic prophylaxis. Only two retrospective studies from 1984 and 1986 were available when planning our study in 2018. 2,3 The confidence intervals in those studies were wide and indicated that rates of sepsis might be 8-13% higher or 3-16% lower without antibiotic prophylaxis than with antibiotic prophylaxis. Consequently, they were underpowered to give any conclusion on the effect of antibiotic prophylaxis.
In the absence of reliable data, we believe that transrectal biopsies, the most commonly used biopsy method in this field, were relevant to consider in the planning of our study. By choosing a 4% limit, we could compare sepsis rates between the study populations and compare results to the most commonly used biopsy method applied worldwide. However, the lower non-inferiority limits proposed by Singhal and colleagues would require the inclusion of several thousand patients, which is practically impossible for most centres.
Singhal and colleagues also claim that use of χ² statistics for sample size estimation was inappropriate and that the recommended test is the Farrington-Manning test. We were unfamiliar with the Farrington-Manning test, but acknowledge it is an alternative. However, our position remains that χ² statistics are used widely and are appropriate for assessing dichotomous outcomes in two independent populations.
The idea of post-hoc sample size estimation and power analyses is fundamentally flawed and it is highly inappropriate to do such analyses when interpreting observed results. 4 The power of observed effects is evident from the width of the confidence intervals or the size of the p values.
We found a difference in sepsis rates of 0·0% (95% CI -1·37 to 1·37), and we find it peculiar that Singhal and colleagues did not make any comments on these results. The width of our 95% CIs indicate that the study was adequately powered and that it is unlikely that the true sepsis rate is higher then 1·37%, making the 4% limit and any post-hoc power analyses irrelevant. Whether clinicians are willing to accept a possible 1·37% higher sepsis rate when performing transperineal biopsies without antibiotic prophylaxis versus with an antibiotic prophylaxis is another question and is open for debate.
Finally, Singhal and colleagues asked whether it is always necessary to conduct an adequately powered trial to change clinical practice. Because current guidelines and most clinicians continue to recommend and use antibiotic prophylaxis despite knowledge obtained from single-arm studies, the obvious answer is yes. The narrow width of the confidence intervals in our randomised controlled trial show that the study is adequately powered, and we believe the study provides new information that adds valuable evidence to current knowledge and, hopefully, tips the balance in favour of omitting routine antibiotic prophylaxis. Omitting routine antibiotic prophylaxis was also encouraged in a recent editorial citing our study, 5 showing that at least some believe the question is no longer unanswered.
We declare no competing interests. Our study has several limitations, including the potential for unmeasured confounding between vaccinated and unvaccinated individuals. Additionally, although we controlled for week of SARS-CoV-2 infection, it is possible that natural immunity, which we could not sufficiently measure, affected our estimates. Specifically, if many unvaccinated individuals gained undocumented natural immunity during omicron BA.1 or BA.2 waves, this could bias our vaccine effectiveness estimates downward.

*Erik
Our results suggest that two doses of BNT162b2 offered little protection against all BA.4/5 outcomes measured, including hospital admission. A booster (third or fourth dose) did provide protection against BA.4/5, but this protection probably wanes after 3 months against milder outcomes like outpatient, urgent care, or emergency department encounters and after roughly 6 months against BA.4/5related hospitalisation.
Approximately half of individuals who are eligible for a booster vaccination in the USA have not yet received a booster dose, 5 and of those who have, many did so at least 6 months ago. Moreover, only a third of US individuals aged 50 years and older who previously received a booster have received a who had a health-care encounter during this time were unvaccinated and 5997 (25%) had received two doses and 12 566 (52%) had received three doses of BNT162b2 vaccine (appendix p 3). Median age was 44 years (IQR 32-58), 15 755 (65%) patients were women, 8599 (35%) were men, fewer than six (<1%) had missing sex data, 12 536 (51%) were Hispanic, 5726 (24%) were White, 2519 (10%) were Asian, 2068 (8%) were Black, and 1507 (6%) were other races or ethnicities. Participant characteristics by vaccination status and outcome are shown in the appendix (pp 4-6). In adjusted analyses, point estimates for vaccine effectiveness against BA.4/5 after two doses were 50% or lower (albeit with wide 95% CIs for most estimates), regardless of outcome and time since last dose (table). At less than 6 months after a third dose of vaccine, vaccine effectiveness was 73% (95% CI 25-91) against BA.4/5related hospitalisation; however, point estimates were less than 50% against milder outcomes (  second booster. 5 Thus, much of the US population-and other populations globally-probably have low levels of vaccine-derived immunity, underscoring the importance of booster programmes. The degree to which protection will be extended by BA.4/5-adapted vaccines in the real-world setting, however, is still unknown and requires future assessments in the months ahead.