Vaccine effectiveness of primary series and booster doses against covid-19 associated hospital admissions in the United States: living test negative design study

Abstract

Objective To compare the effectiveness of a primary covid-19 vaccine series plus booster doses with a primary series alone for the prevention of hospital admission with omicron related covid-19 in the United States. Design Multicenter observational case-control study with a test negative design. Setting Hospitals in 18 US states. Participants 4760 adults admitted to one of 21 hospitals with acute respiratory symptoms between 26 December 2021 and 30 June 2022, a period when the omicron variant was dominant. Participants included 2385 (50.1%) patients with laboratory confirmed covid-19 (cases) and 2375 (49.9%) patients who tested negative for SARS-CoV-2 (controls). Main outcome measures The main outcome was vaccine effectiveness against hospital admission with covid-19 for a primary series plus booster doses and a primary series alone by comparing the odds of being vaccinated with each of these regimens versus being unvaccinated among cases versus controls. Vaccine effectiveness analyses were stratified by immunosuppression status (immunocompetent, immunocompromised). The primary analysis evaluated all covid-19 vaccine types combined, and secondary analyses evaluated specific vaccine products. Results Overall, median age of participants was 64 years (interquartile range 52-75 years), 994 (20.8%) were immunocompromised, 85 (1.8%) were vaccinated with a primary series plus two boosters, 1367 (28.7%) with a primary series plus one booster, and 1875 (39.3%) with a primary series alone, and 1433 (30.1%) were unvaccinated. Among immunocompetent participants, vaccine effectiveness for prevention of hospital admission with omicron related covid-19 for a primary series plus two boosters was 63% (95% confidence interval 37% to 78%), a primary series plus one booster was 65% (58% to 71%), and for a primary series alone was 37% (25% to 47%) (P<0.001 for the pooled boosted regimens compared with a primary series alone). Vaccine effectiveness was higher for a boosted regimen than for a primary series alone for both mRNA vaccines (BNT162b2 (Pfizer-BioNTech): 73% (44% to 87%) for primary series plus two boosters, 64% (55% to 72%) for primary series plus one booster, and 36% (21% to 48%) for primary series alone (P<0.001); mRNA-1273 (Moderna): 68% (17% to 88%) for primary series plus two boosters, 65% (55% to 73%) for primary series plus one booster, and 41% (25% to 54%) for primary series alone (P=0.001)). Among immunocompromised patients, vaccine effectiveness for a primary series plus one booster was 69% (31% to 86%) and for a primary series alone was 49% (30% to 63%) (P=0.04). Conclusion During the first six months of 2022 in the US, booster doses of a covid-19 vaccine provided additional benefit beyond a primary vaccine series alone for preventing hospital admissions with omicron related covid-19. Readers’ note This article is a living test negative design study that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication.

Absolute and Relative Vaccine Effectiveness of Primary and Booster Series of COVID-19 Vaccines (mRNA and Adenovirus Vector) Against COVID-19 Hospitalizations in the United States, December 2021–April 2022

“…Although chronic conditions have been observed to reduce effectiveness [ 30 ], sample size was insufficient to differentiate VE by number of conditions. Fourth, the influence of prior infection on VE is not fully known due to a lack of definitive prior infection history among hospitalized patients (eg, inability or refusal to answer) and the likelihood of undercapture [ 31 ]; however, a previous sensitivity analysis showed that effectiveness did not change after removing patients with prior infection [ 13 ]. Fifth, it was not possible to estimate potential waning of VE due to the time-limited nature of the study, but previous analyses have shown waning for booster doses with increasing time since vaccination [ 6 ].…”

“…During December 25, 2021–April 4, 2022, a period in which the B.1.1.529 (Omicron) variant of SARS-CoV-2 was close to 100% predominant (including an estimated >90% BA.1 or BA.2 lineages) [ 13 ], adults admitted to 21 hospitals in 18 US states within the Influenza or Other Viruses in the Acutely Ill (IVY) Network [ 2 , 4 , 14 , 15 ] who received testing for SARS-CoV-2 were included in a VE analysis. The analysis start date of December 25, 2021 was approximately 1 month after the emergency use authorization of a first booster dose (following a primary series of 2 mRNA doses or 1 Janssen dose) was expanded to include all adults aged ≥18 years [ 16 ] and coincided with the start of the period when the SARS-CoV-2 Omicron variant dominated in the United States.…”

“…We estimated aVE and rVE using multivariable logistic regression, where the odds ratio (OR) is modeled with case-status as the outcome and vaccination group (vaccinated without booster, vaccinated with booster, or unvaccinated, depending on analysis) as the exposure of interest while adjusting for sex, race/ethnicity, US Census region of the admitting hospital, age, number of pre-existing conditions, and admission date (biweekly intervals). Covariates were selected a priori based on clinical knowledge and past IVY analyses [ 2 , 4 , 13 , 14 ]. The VE was calculated as (1-OR) × 100% [ 17 ].…”

Characterization of SARS-CoV-2 recombinants and emerging Omicron sublineages

“…A bivalent mRNA vaccine ("updated vaccine") booster containing components of the original (ancestral) strain and the BA.4/BA.5 is recommended [80]. This was supported by Adams et al, who observed that an mRNA vaccine booster dose provided additional benefit beyond a primary vaccine series alone for preventing hospital admissions with Omicron related COVID-19 during the first six months of 2022 in the US [81]. In addition, a Phase Ⅱ/Ⅲ clinical trial (NCT04927065) reported that 50 μg bivalent Omicron-containing booster mRNA vaccine (named mRNA-1273.214, Moderna), which combines mRNA-1273.529 and mRNA-1273, elicited higher neutralizing antibody response against BA.4/5 than immune response elicited with mRNA-1273 28 days after immunization, without evident safety concerns.…”

Considerations in Understanding Vaccine Effectiveness

“…When the Delta variant became predominant (from early to late 2021), overall, VE in preventing breakthrough infections was reduced from 90% to 78–81% [ 16 ]. When we experienced the Omicron wave from late 2021 to early 2022, the BNT162b2 vaccine showed reduced effectiveness in preventing symptomatic SARS-CoV-2 infection compared to during the Delta wave period [ 17 ], with recommendations for a booster vaccination to be given to prevent Omicron-related hospitalization/illness [ 18 , 19 ]. With the advent of newer variants (e.g., BA.4, BA.5, XBB) with enhanced immune evasion [ 20 , 21 ], VE against hospitalization was further compromised [ 22 ], with calls for additional doses of bivalent vaccine to improve protection [ 23 , 24 ].…”