By using data from December 23, 2021, to February 21, 2022, we investigated prior infection with variants other than omicron, vaccination with two or three doses of the COVID-19 messenger RNA vaccine BNT162b2 or mRNA-1273, and mixed immunity.

Editor: Han Xiaose

Summary: Recently, new coronavirus infections have mainly shifted from BA.1 to BA.2 sub-variants. Although BA.1 and BA.2 are still classified as subvariants of omicron, there is a considerable genetic distance between them. Previous immunity provided protection against these sub-variants—

Recent new coronavirus infection has mainly shifted from the BA.1 to the BA.2 sub-variant. Although BA.1 and BA.2 are still classified as subvariants of omicron, there is a considerable genetic distance between them. Whether previous immunity confers protection against these subvariants—and whether immunity results from previous infection, vaccination, or a mixture of the two—remains to be established.

By using data from December 23, 2021 to February 21, 2022, we investigated prior infection with variants other than omicron, vaccination with two or three doses of coronavirus disease 2019 (Covid-19) messenger RNA ( mRNA) vaccine BNT162b2 (Pfizer–BioNTech) or mRNA-1273 (Moderna) and mixed immunity (previous infection and vaccination).

Efficacy was evaluated against symptomatic BA.1 infection, symptomatic BA.2 infection, and any symptomatic omicron infection. Protection against any severe (acute care hospitalization), critical (intensive care unit hospitalization), or fatal case due to BA.1, BA.2, or any omicron infection was also evaluated.

The study was conducted among the resident population of Qatar. We analyzed information on Covid-19 vaccinations, laboratory tests, hospitalizations and deaths from a joint national database. The data were taken from the National Integrated Digital Health Information Platform. These databases include all SARS-CoV-2-related data and related demographic information since the beginning of the pandemic. These databases include results from all PCR) tests, as well as recent rapid antigen tests performed in healthcare settings after January 5, 2022.

All PCR tests (but not rapid antigen tests) conducted in Qatar are categorized according to symptoms and reason for testing. Of all PCR tests performed during this study, 19.2% were performed due to clinical symptoms. Qatar has an unusually young, diverse population—only 9% of residents are 50 years or older, and 89% are expatriates from more than 150 countries. Qatar launched its Covid-19 vaccination program in December 2020 with its BNT162b2 and mRNA-1273 vaccines.

This study evaluated the effectiveness of prior infection, BNT162b2 or mRNA-1273 vaccination, and mixed immunity (prior infection and vaccination) against symptomatic infection with BA.1, BA.2, and any omicron infection. We used a negative case-control design, in which effectiveness estimates are derived by comparing the odds of case participants (people with a positive PCR test) with controls (people with a negative PCR test) of previous infection or vaccination, or both. We also evaluated effectiveness against any severe, critical or fatal cases of Covid-19.

To estimate effectiveness against symptomatic infection, we fully matched cases and controls identified from December 23, 2021, to after February 21, 2022. Case participants and controls were matched 1:1 by sex, age group, to control for known differences in risk of exposure to SARS-CoV-2.

We compared the five groups with previously uninfected and unvaccinated groups. Five groups were characterized by exposure type: past infection and no vaccine, two doses of vaccine and no infection, two doses of vaccine and past infection, three doses of vaccine and no infection, three doses of vaccine and past infection. The groups are The PCR test was defined by status of a previous immune event (previous infection or vaccination).

From December 23, 2020 (the date when vaccinations started in Qatar) to February 21, 2022 (the end of the study), 1,306,862 people received at least two doses of BNT162b2, of whom 341,438 received a third dose (booster).The median date of the first dose was May 3, 2021, the median date of the second dose was May 24, 2021, and the median date of the third dose was December 25, 2021.

The median interval between the first and second doses was 21 days (interquartile range, 21 to 22), and the median interval between the second and third doses was 251 days (interquartile range, 233 to 274). The narrow interquartile range between first and second doses reflects strict compliance with state policy.

During the study period, 893,671 people received two doses of mRNA-1273, with 135,050 receiving the third dose. The median date of the first dose was May 28, 2021, the median date of the second dose was June 27, 2021, and the median date of the third dose was January 12, 2022. The median interval between the first and second doses was 28 days (interquartile range, 28 to 30) and the time between the second and third doses was 236 days (interquartile range, 213 to 260). Table 1 shows the characteristics of these groups.

Prior infection and unvaccinated efficacy against symptomatic BA.1 infection was 50.2% (95% confidence interval [CI], 38.1 to 59.9) (Fig. 1A and Table 2). The median interval between previous infection and the PCR test used in the study was 324.5 days (range, 91 to 643; interquartile range, 274 to 497).

Vaccination with two doses of BNT162b2 and no previous infection had negligible effectiveness (-4.9%; 95% CI, -16.4 to 5.4). The median interval between the second vaccination and the PCR test used in the study was 268 days (range, 15 to 394; interquartile range, 211 to 293). Efficacy at three doses without prior infection was 59.6% (95% CI, 52.9 to 65.3). The median interval between the third dose and the PCR test used in the study was 42 days (range, 7 to 291; interquartile range, 28 to 62).

The effectiveness of mixed immunity (prior infection and two doses of BNT162b2) was 51.7% (95% CI, 43.5 to 58.7), which was similar to the effectiveness of prior infection alone. Prior infection and three doses of BNT162b2 had the highest efficacy at 74.4% (95% CI, 63.4 to 82.2).

Prior infection, vaccination and mixed immunity all showed strong effectiveness (90%) against severe, critical or fatal Covid-19 from BA.1 infection, but due to low case numbers, partially 95% The confidence intervals were wide (Figure 1B and Table 2). The severity of BA.1 infections was low, with only 0.3% (95% CI, 0.2 to 0.4) of infections progressing to severe, critical or fatal Covid-19.

Prior infection and unvaccinated efficacy against symptomatic BA.2 infection was 46.1% (95% CI, 39.5 to 51.9) (Fig. 1C and Table 2). The median interval between previous infection and the PCR test used in the study was 319 days (range, 90 to 662; interquartile range, 275 to 499).

The effectiveness of two doses of BNT162b2 and no previous infection was negligible (-1.1%; 95% CI, -7.1 to 4.6). The median interval between the second vaccination and the PCR test used in the study was 270 days (range, 14 to 399; interquartile range, 213 to 296). The efficacy of three doses of BNT162b2 in the absence of prior infection was 52.2% (95% CI, 48.1 to 55.9). The median interval between the third dose and the PCR test used in the study was 43 days (range, 7 to 322; interquartile range, 26 to 65).

The effectiveness of prior infection and two doses of BNT162b2 was 55.1% (95% CI, 50.9 to 58.9), which was similar to the effectiveness of prior infection alone. Prior infection and three doses of BNT162b2 had the highest efficacy at 77.3% (95% CI, 72.4 to 81.4).

Previous infection, vaccination and mixed immunity all showed strong effectiveness (70%) against causing severe, critical or fatal Covid-19 in BA.2, but some of the 95% confidence intervals were narrow due to the small number of cases. wide (Figure 1D and Table 2). BA.2 infections were less severe, with only 0.3% (95% CI, 0.2 to 0.3) of infections progressing to severe, critical or fatal Covid-19.

The effectiveness of prior infection, BNT162b2 vaccination, and mixed immunity against any symptomatic omicron infection showed a similar pattern to that against BA.1 and BA.2 (Fig. 2A and Table 2). Effectiveness against severe, severe or fatal Covid-19 due to any omicron infection also showed a similar pattern to BA.1 and BA.2 for these outcomes (Figure 2B and Table 2).

Effectiveness of prior infection, vaccination, and mixed immunity against any symptomatic Omicron infection according to time since prior infection or vaccination.

Analysis of effectiveness as a function of time for past infection, two-dose vaccination, and three-dose vaccination since an immune event (previous infection or vaccination) shows that vaccine protection wanes rapidly after the second and third doses , but the protective effect of previous infection against immune events slowly diminishes.

The effectiveness of prior infection, vaccination, and mixed immunity in the mRNA-1273 analysis showed a similar pattern to the BNT162b2 analysis.

Booster vaccination is associated with an approximately 60% reduction in the risk of infection. There was no significant difference in protection between BA.1 and BA.2 by booster vaccination. However, most people received their third dose less than 45 days ago, which may explain the relatively high effectiveness.

Combined immunity from prior infection and two doses of vaccination conferred protection similar to prior infection alone, approximately 50%, suggesting that this protection resulted from prior infection rather than vaccination.

No significant differences were observed in the effectiveness of previous infection, vaccination and mixed immunization against BA.1 and BA.2. Previous protection against reinfection with variants other than omicron was modest and long-lasting, but protection against primary series vaccination was negligible at 6 months after the second dose.

Recent booster vaccination had a moderate effect, whereas mixed immunity to previous infection and a recent booster vaccination had the strongest protective effect against infection, around 80%. However, all five forms of immunity were associated with strong and durable protection against hospitalization and death from Covid-19, especially protection against severe disease and death with two doses of vaccine + infection, three doses of vaccine, or three doses + infection above 90%.