Israel Study Reveals Gradual Increase In COVID Infection Risk 90 Days After Second Pfizer Vaccine Dose

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A new study by researchers from Leumit Health Services-Israel, Ariel University, Ariel-Israel, Tel Aviv University-Israel, Barzilai University Medical Centre and also involving experts from the National Cancer Institute, Bethesda-USA has found a gradual increase in the risk of COVID-19 infection from 90 days after receiving a second dose of the Pfizer-BioNTech vaccine.

In the study, 83,057 adults received an RT-PCR test for SARS-CoV-2 during the study period and 9.6% had a positive result.

Time elapsed since the vaccine injection was significantly longer in individuals who tested positive (P<0.001).

Adjusted odds ratio for infection at time intervals >90 days since vaccination were significantly increased compared with the reference of <90 days: 2.37 (95% confidence interval 1.67 to 3.36) for 90-119 days, 2.66 (1.94 to 3.66) for 120-149 days, 2.82 (2.07 to 3.84) for 150-179 days, and 2.82 (2.07 to 3.85) for ≥180 days (P<0.001 for each 30 day interval).

The study findings showed that in this large population of adults tested for SARS-CoV-2 by RT-PCR after two doses of mRNA BNT162b2 vaccine, a gradual increase in the risk of infection was seen for individuals who received their second vaccine dose after at least 90 days.

The study findings were published in the peer reviewed British Medical Journal. 

https://www.bmj.com/content/375/bmj-2021-067873

Immunity to SARS-CoV-2 can be induced by SARS-CoV-2 infection or vaccination. Individuals who are immune have some protection against reinfection and a reduced risk of severe clinical consequences.1

Recovering seropositive adult individuals have about 90% protection from SARS-CoV-2 reinfection after 150 days,2 and distinguishing reinfection from the effects of the initial infection is challenging before 90 days.3

In contrast, vaccination has been reported to be 50-95% effective at various time points.456 Nevertheless, the memory B cell humoral response and spike specific CD4+ cellular immune responses to SARS-CoV-2 are predictably diminishing over time.78

Therefore, concerns have been raised about a possible reduction in SARS-CoV-2 immune protection in vaccinated populations and in those who have recovered from covid-19 disease.9

Israel was among the first countries to initiate a large scale vaccination campaign on 20 December 2020. A large proportion of the population were quickly immunised, partly because of the centralised health services and the decision to use only one vaccine, achieving early control over the spread of the virus.10 11 12

Up to 26 July 2021, more than 5.2 million Israelis were fully vaccinated with two doses of the Pfizer-BioNTech vaccine.13 Since June 2021, however, a resurgence of individuals with SARS-CoV-2 has been seen, which could be at least partially because of decreasing levels of anti-SARS-CoV-2 antibodies in vaccinated people.14

Here, we describe the results of a large scale study measuring the association between time elapsed since administration of the second dose of the Pfizer-BioNTech BNT162b2 vaccine and the risk of covid-19 disease.

Discussion
Principal findings

In this large population of individuals who received two doses of the Pfizer-BioNTech BNT162b2 vaccine, we found a significantly (P<0.001) higher risk of SARS-CoV-2 infection with time elapsed since the second vaccine dose, after the initial 90 days (reference category).

The increase was seen in the pre-matched cohort and was confirmed in a cohort matched for week of testing, age categories, and demographic group, and further adjusted for sex, age, socioeconomic status, and chronic comorbid conditions. These findings confirm that the BNT162b2 vaccine provided excellent protection in the initial weeks after vaccination but suggest that protection wanes for some individuals with time.

The principal initial study that led to the US Food and Drug Administration emergency use authorisation for the BNT162b2 vaccine provided safety and efficacy data for a median time of more than two but less than three months, understandably balancing the objectives of beginning mass vaccinations and having some time course data.19

The stopping criterion in the study was based on the balance of individuals with covid-19 in the vaccinated versus unvaccinated cohorts, and not on a fixed amount of time.19 The study also showed that two injections, 21 days apart, provided more protection than one, and that the immune response to the vaccines was influenced by changes in the immune system related to age.20

Implementation of a third injection in immunocompromised individuals and older individuals has been adopted by several health authorities, including in Israel,21 22 23 with observed real world data in our population.

Strengths of the study

The strengths of our analysis include the use of a large cohort of individuals vaccinated twice, all of whom received the same vaccine, with detailed demographic and clinical information, and continuously updated data on vaccination and past and new SARS-CoV-2 infections. Israel was one of the first countries to rollout a large scale vaccination campaign, and individuals in our study received their second vaccine injection up to six months ago.

The study design allowed us to quantify the increase in the risk of covid-19 with increasing time from the second injection. Throughout the study period, most of the new infections were caused by the delta variant (B.1.617.2) of SARS-CoV-2 (93% of 113 isolates sent for sequencing in the Leumit Health Services organisation), and hence our study reflects the protection offered by the vaccine against the now dominant worldwide SARS-CoV-2 strain that was not prevalent in earlier studies of the vaccine.

In the Leumit Health Services organisation, RT-PCR tests are provided with no limit on the number of requests from patients or physicians, allowing a high detection rate of covid-19 infection before and during the study period. In initial analyses, we found that among individuals who had evidence of past infection and who received a RT-PCR test during the same study period, the infection rate was 4.7% for unvaccinated individuals and 3.8% for vaccinated individuals (v 9.6% infection rate among vaccinated individuals with no evidence of past infection).

Given the significantly different rate of infection found in individuals with previous covid-19 (P<0.001), we excluded individuals with evidence of past infection from the study cohort.

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