key: cord-0911719-pv4rcmjb authors: Mor, Orna; Zuckerman, Neta S.; Hazan, Itay; Fluss, Ronen; Ash, Nachman; Ginish, Netanel; Mendelson, Ella; Alroy-Preis, Sharon; Freedman, Laurence; Huppert, Amit title: BNT162b2 vaccine effectiveness was marginally affected by the SARS-CoV-2 beta variant in fully vaccinated individuals date: 2021-10-29 journal: J Clin Epidemiol DOI: 10.1016/j.jclinepi.2021.10.011 sha: b6d57319f02e6ee25af66432249ab181578c5d93 doc_id: 911719 cord_uid: pv4rcmjb OBJECTIVE: To evaluate the effectiveness of the Pfizer BNT162b2 vaccine against the SARS-Cov-2 Beta variant. STUDY DESIGN AND SETTING: Israel's mass vaccination program, using two doses of the Pfizer BNT162b2 vaccine, successfully curtailed the alpha variant outbreak during winter 2020-21, However, the virus may mutate and partially evade the immune system. To monitor this, sequencing of selected positive swab samples of interest was initiated. Comparing vaccinated with unvaccinated PCR positive persons, we estimated the odds ratio for a vaccinated case to have the Beta versus the Alpha variant, using logistic regression, controlling for important confounders. RESULTS: There were 19 cases of Beta variant (3.2%) among those vaccinated more than 14 days before the positive sample and 79 (3.4%) among the unvaccinated. The estimated odds ratio was 1.26 [95% CI: 0.65-2.46]. Assuming the effectiveness against the Alpha variant to be 95%, the estimated effectiveness against the Beta variant was 94% [95% CI: 88-98%]. CONCLUSION: Despite concerns over the Beta variant, the BNT162b2 vaccine seemed to provide substantial immunity against both that Beta and the Alpha variants. From 14 days following the second vaccine dose the effectiveness of BNT162b2 vaccine was at most marginally affected by the Beta variant. The impressive success of mass vaccination in curtailing the coronavirus 2 (SARS-CoV-2) by halting transmission has paved the road for returning to "pre-pandemic life". However, several open questions challenge the triumph of controlling the pandemic by vaccination. One major concern is the ability of the virus to mutate and evolve; this potentially can cause SARS-CoV-2 to partially evade the immune system, reducing vaccine effectiveness (VE) in preventing disease and viral transmission. Determining VE against variants of concern (VOC) 1 is vital for planning and modifying vaccination strategies. On December 19 th 2020, Israel launched a massive COVID vaccination campaign based on the Pfizer BNT162b2 vaccine, and by end of May 2021, had administered over 10,500,000 doses, to approximately 5,400,000 individuals, more than 80% of the population over 16y receiving two doses. Both in clinical trials and real world studies, the vaccine has proven highly effective in both averting infections and preventing severe disease and death. [2] [3] [4] [5] The Israeli vaccination campaign took place during the third and largest wave of the pandemic (see Figure 1 ). During this wave, the Alpha variant became the dominant strain in Israel, reaching over 95% dominance. 6 Since detection of the Alpha variant in November 2020 in the United Kingdom, it spread rapidly and became the dominant strain in many countries. There is also evidence that it caused higher rates of morbidity and mortality. 7 Nevertheless, the BNT162b2 vaccine, which was developed based on the original Wuhan strain sequence, has 4 been found very effective against the Alpha variant, both in blocking transmission and reducing morbidity and mortality following infection. [2] [3] [4] [5] The Beta variant, first documented in South Africa, is also considered a VOC mainly because in vitro experiments demonstrated its ability to overcome previous immunity to SARS-CoV2. Specifically, experimental work demonstrated significant decrease in neutralization capacity of the Beta variant. 8 However other research found that neutralizing antibodies remained sufficiently high against this variant. 9 Humoral protection measured by antibody responses and neutralization studies do not assess the role of cellular immunity mediated by T-cell responses. A recent study showed that cellular protection established following previous infection or vaccination remains high against both Alpha and Beta variants. 10 However, two real world studies have raised concern that the BNT162b2 vaccine has reduced effectiveness against the Beta variant. A study from Qatar showed that the effectiveness of BNT162b2 against the Beta variant was ~75% compared to ~90% against the Alpha variant. 11 A second study from Israel estimated that the odds ratio (OR), in a matched study of SARS-Cov-2 cases occurring in unvaccinated persons versus persons who had received their second dose of vaccine at least one week previous to sample collection, was 1/8, implying considerably lower VE against the Beta variant. 6 Thus, our goal was to further quantify the risk of the Beta variant causing a significant breakthrough in a real world environment. With the start of the vaccination campaign in Israel, the Central Virology Laboratory (CVL) of the Ministry of Health, initiated collection and sequencing of selected swab samples that had tested positive on polymerase chain reaction (PCR). Samples were selected for sequencing to i) monitor the circulating and imported variants in Israel, ii) characterize viral variants among cases occurring after vaccination and matching cases in unvaccinated persons iii) monitor local outbreaks, severe clinical cases and transmission among specific population groups, and iv) follow-up those coming into contact with persons infected with the Beta variant. Samples identified as being of interest were retrieved from the 48 laboratories that perform SARS-CoV-2 PCR tests in Israel, and sent to CVL, where they were assessed by whole genome sequencing. Information on all cases sent for sequencing was entered in a database, containing: sociodemographical variables (e.g. age, city/town/village of residence, subpopulation -Arab, Ultra-Orthodox Jewish, other), date of collection of first positive sample, date of recovery, vaccination 6 dates, symptoms and hospitalizations, and the infecting variant as determined by whole genome sequencing. All information was retrieved from the Israeli Ministry of Health's databases. Our analyses were restricted to vaccinated and unvaccinated cases that were positive either for the Alpha variant or the Beta variant, using whole genome sequencing. Vaccinated cases were defined as those where the first positive sample was taken at least 14 days after the second dose. Those with unknown dates of vaccination, or who received only one vaccine dose, or for whom the sample was taken between the first dose and second dose, were excluded. Cases based on samples taken before January 1 st 2021 were also excluded, because no persons were fully vaccinated before that date. Those for whom the sample was taken less than 14 days after their second dose were excluded from the main analysis, but were included in a secondary analysis. Individuals who had acquired the infection outside Israel, those aged less than 16y (not eligible for vaccination) and individuals without information regarding their place of residence, were all excluded. The main principle of the statistical analysis was to estimate the odds ratio, OR, for a vaccinated case to have the Beta variant, within vaccinated and unvaccinated persons who tested positive. One can show (see Supplementary Information) that: 13 This approach also provided a p-value for the test that OR=1 and a 95% confidence interval for the OR. A secondary analysis was conducted to examine the influence of time of infection following full vaccination, using the same methods as described above and comparing unvaccinated cases versus cases where the sample from the vaccinated case was taken within the first 14 days after the second dose of vaccination. Alternative analyses were conducted using matching to control for confounding variables, and are reported in the Supplementary Information. Unlike the main analyses presented here, such matching entails exclusion of approximately 60% of the cases. We regard their results as providing information supportive to the main analyses. The database contained the sequencing results of 11624 samples obtained from distinct individuals. After the exclusions described in the Methods section, 596 vaccinated and 2333 unvaccinated cases were left eligible for analysis ( Figure 2 ). Characteristics of these vaccinated and unvaccinated individuals are shown in Table 1 , and according to variant in Table A1. The 8 vaccinated groups were on average older and had a smaller proportion of ultra-orthodox Jews.. Variant Beta appeared more in the Arab sector and less among Ultra-orthodox Jews. These differences emphasize the need to control for these potential confounders. The proportion of the Beta variant (versus the Alpha) in the dataset over the period of our study is shown in Figure 1 . The distribution of variants (Alpha and Beta) by vaccination status is shown in large drop in sensitivity of the Alpha variant to sera collected from vaccinated individuals and an even larger reduction in sensitivity to convalescent sera. 8 The Beta variant has caused further anxiety regarding the potential vaccine breakthrough due to the co-occurrence of supplementary mutations in the receptor-binding domain, which were proven to have a significantly increased resistance to vaccine-induced and convalescent sera. 15 Two real-world studies which examined the protection of the BNT162b2 vaccine against Alpha and Beta variants found a substantial reduction in VE against Beta compared to Alpha. 6, 11 Results from a previous study in Israel based on a matched pairs case-case design pointed to a Limitations of our study include the relatively low number of Beta variant cases, owing to its low prevalence in Israel, and also the fact that the sequencing was not done on a sample selected randomly from the total population of SARS-Cov2 positive cases in Israel. 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