Our data provide evidence of waning of protection against symptomatic infection after the receipt of two doses of the ChAdOx1-S or BNT162b2 vaccine from 10 weeks after receipt of the second dose. Protection against hospitalization and death, however, was sustained at high levels for at least 20 weeks after receipt of the second dose. At 20 weeks or more after receipt of the second dose, we observed more waning with the ChAdOx1-S vaccine than with the BNT162b2 vaccine, although the groups who received each vaccine differed.6 Waning of protection against hospitalization was greater in older adults and in participants in a clinical risk group. Among persons 65 years of age or older who were not in a clinical risk group, however, protection against hospitalization remained close to 95% with the BNT162b2 vaccine and just under 80% with the ChAdOx1-S vaccine at 20 weeks or more after receipt of the second dose.
Our finding of waning of vaccine effectiveness against symptomatic disease is consistent with recent findings from Israel and Qatar that showed an increasing proportion of breakthrough cases among persons who had received vaccines the earliest.9,17-19 In addition to the emergence of the more transmissible delta variant, waning protection against symptomatic infection with increasing time since vaccination is also probably contributing to the increase in the incidence of Covid-19 in the United Kingdom and elsewhere. However, the incidence of Covid-19–related hospitalization and death has remained low, especially among vaccinated adults.20 Our finding of only limited waning of protection against hospitalization or death in most groups that we studied is consistent with the preserved vaccine effectiveness against hospitalization that was observed in Qatar.9
Regional U.S. studies have also shown sustained high vaccine effectiveness against Covid-19–related hospitalization despite the emergence and rapid local spread of the delta variant. Across 18 U.S. states, vaccine effectiveness after the receipt of two vaccine doses administered 3 weeks apart among adults (median age, 59 years) who had been admitted to 21 hospitals during the period from March 11 to July 14, 2021, was 86% (95% CI, 82 to 88) overall; vaccine effectiveness was 87% (95% CI, 83 to 90) among patients with illness onset during the period from March through May, as compared with 84% (95% CI, 79 to 89) among those with illness onset during the period of June and July 2021, with no evidence of a significant decrease in vaccine effectiveness over the 24-week period.21 A similar study involving adults in New York during the period from May 3 to July 25, 2021, showed hospitalization rates to be lower by a factor of nearly 10 among vaccinated adults (>90% of whom had received two doses of mRNA vaccine 3 weeks apart) than among unvaccinated adults (1.31 vs. 10.69 per 100,000 person-days). Vaccine effectiveness against hospitalization remained relatively stable (91.9 to 95.3%) during the surveillance period, although the age-adjusted vaccine effectiveness against new cases of Covid-19 decreased from 91.7% to 79.8%, a change that coincided with an increase in the circulation of the delta variant from less than 2% to more than 80% of cases.22 Conversely, reports have appeared of an increased proportion of hospitalization among infected adults who had been vaccinated the earliest and had received two doses of the BNT162b2 vaccine 3 weeks apart in Israel.17 The shorter interval of 3 weeks as well as the longer follow-up in a population with rapid vaccine uptake in Israel may be factors in explaining this difference as compared with findings in the United Kingdom, the United States, and Qatar.
Our findings and those from Qatar and the United States raise important questions about the timing of third doses of vaccine in adults who remain protected against hospitalization and death for at least 5 months after the receipt of two doses. Israel was one of the first countries to immunize adults with the BNT162b2 vaccine and began offering a third dose of the same vaccine to older adults starting in July 2021.23 Early data indicate that the third dose was associated with large reductions in the incidence of SARS-CoV-2 infection within 1 week after vaccination, with greater reductions in the second week.23 The duration of protection offered by the third dose, however, is uncertain. Many countries, including the United Kingdom and the United States, are now offering a third dose.
A third dose of vaccine improves both humoral and cellular immunity against SARS-CoV-2, with increased neutralizing activity against different variants, including the delta variant, which is likely to improve protection against infection.24 Waning of vaccine effectiveness against severe disease outcomes was relatively limited in most cohorts in this study but is likely to continue with time since the receipt of two vaccine doses. Decisions on timing of the third dose must balance the rate of waning immunity against the prevalence of disease, including the risk of new variants, and the prioritization of persons at highest risk for severe disease. Existing evidence suggests that vaccine effectiveness increases with longer intervals between doses and, if this also applies to third doses, the administration interval will also need to be considered.25 At the same time, it is possible that third doses will be more reactogenic than previous doses, especially if the recipient receives different vaccines for the initial and booster doses.26 Attractive alternatives include half-dose boosters or boosting with variant-targeted vaccines, which are both under investigation.27
For the United Kingdom and countries with administration intervals that are longer than the licensed interval, another important consideration is that the extended interval of 8 to 12 weeks between vaccine doses provides higher serologic responses and increased vaccine effectiveness than the licensed interval of 3 to 4 weeks for mRNA vaccines,25 which may provide the populations in these countries with better, longer-term protection.12 This hypothesis is supported by our current findings comparing short and long administration intervals among persons 80 years of age or older.
We found that waning effectiveness against hospitalization was greatest among persons in clinical risk groups. Other studies have shown lower immune responses and vaccine effectiveness among persons in clinical risk groups, most notably those with immunosuppression.10,21,28,29 The United Kingdom and other countries already recommend a third dose of Covid-19 vaccine for all adults as part of their primary immunization course.30,31
This study has some limitations. The test-negative case–control study design is observational and, therefore, subject to potential bias. The very narrow 95% confidence intervals in some analyses relate to the large sample size and do not account for what may be relatively larger effects of bias. A detailed quantification of potential bias is beyond the scope of this article, but others have assessed some biases such as exposure and outcome misclassification when using the test-negative design for hospitalized case and control participants.32 A full discussion of these limitations is provided in Section S3. The likely direction of these biases, if they exist, would be to reduce vaccine effectiveness, with the reduction being greater with longer intervals after vaccination. Other limitations include our limited ability to assess waning vaccine effectiveness against the alpha variant owing to low circulation since June 2021. In addition, these estimates of vaccine effectiveness relate to the population of persons who seek testing and were successfully matched to the NIMS database, so they may not be representative of the whole population. For example, a higher proportion of non-White persons than White persons do not match to the NIMS database. We also relied on tested persons declaring their symptoms when the test was requested, and some asymptomatic persons may declare symptoms in order to access the test. Overall vaccine effectiveness will be attenuated if it is lower against asymptomatic infection and, for control participants, may mean that they were not matched on the basis of exposure to an infectious disease that led to symptoms.
Our study showed evidence of significant waning of vaccine effectiveness against symptomatic disease, but with limited waning against severe disease, for at least 5 months after an extended-interval, two-dose schedule with the ChAdOx1-S and BNT162b2 vaccines. Waning vaccine effectiveness was greater among older adults and among adults in clinical risk groups.