Effectiveness of homologous and heterologous Covid-19 boosters against Omicron

For the editor:

For people who have received a single dose of the Ad26.COV2.S (Johnson & Johnson–Janssen) coronavirus disease 2019 (Covid-19) vaccine, a booster dose of at least one messenger RNA (mRNA) vaccine 2 months after the primary vaccination dose is recommended. Ad26.COV2.S recipients for the primary and booster doses may receive a second booster dose of a Covid-19 mRNA vaccine at least 4 months after the first Ad26.COV2.S booster dose.1 Immunogenicity data from a Phase 1–2 clinical trial conducted prior to the emergence of B.1.1.529 and omicron BA sublines showed that increases in binding and neutralizing antibody titers with heterologous boost were similar to or greater than increases with homologous boost.2 In a study involving US veterans, data obtained during a period in which omicron was the predominant circulating variant also showed that among Ad26.COV2.S recipients, vaccine efficacy against omicron infection was higher with heterologous boost than with homologous boost.3; however, data from the general adult population and on vaccine effectiveness over time are lacking. Over 18 million doses of the Ad26.COV2.S vaccine have been administered in the United States alone4; therefore, data are needed on effective reinforcement strategies over time.

We performed a test-negative case-control analysis to assess the efficacy of four vaccination regimens against symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during a period when omicron was the variant predominantly circulating: a single dose of Ad26.COV2.S, a single priming dose of Ad26.COV2.S plus a booster dose of Ad26.COV2.S (Ad26.COV2.S/Ad26.COV2. S), a single priming dose of Ad26.COV2.S plus a booster dose of mRNA vaccine (Ad26.COV2.S/mRNA), and two priming doses of an mRNA vaccine plus a mRNA vaccine booster (mRNA/mRNA/mRNA). In regimens that included an mRNA vaccine, either the BNT162b2 vaccine (Pfizer-BioNTech) or the mRNA-1273 vaccine (Moderna) was used. The methods have been published previously5 and are described in the Supplementary Appendix, available with the full text of this letter on NEJM.org.

A total of 512,928 rapid and laboratory-based nucleic acid amplification tests (NAATs) were used in the current study; the tests were obtained between January 2 and March 23, 2022 from the Increasing Community Access to Testing (ICATT) platform, which facilitates free, drive-through SARS-CoV-2 testing at pharmacies.5 In our analysis, we included tests of adults 18 years of age or older who reported their vaccination status (product and month and year each dose was received) and at least one Covid-19-like symptom, which most likely reflected mild illness. The tests included came from 7,036 testing sites in 49 states, Washington, DC and Puerto Rico. All sites belonged to a single pharmacy chain that obtained information on booster doses during this period. This channel had wide national coverage. During the period this study was conducted, 93.5% of all adult tests provided through the ICATT platform, including those that did not meet our inclusion criteria, were conducted in this channel alone. . Swab specimens were collected by participants onsite and results were either processed onsite by the pharmacy (rapid polymerase chain reaction tests) or sent for processing at contracted laboratories (laboratory NAATs) . All positive tests were assumed to involve the omicron variant, as more than 90% of infections detected nationwide during this period were caused by this variant.4 Tests from people who reported previous SARS-CoV-2 infection were excluded. A sensitivity analysis including testing regardless of prior SARS-CoV-2 infection was performed (see Supplementary Appendix).

Vaccine efficacy (calculated as [1−the odds ratio]×100) of each of the four vaccination regimens, compared to no vaccination, against symptomatic infection during the periods 14 days to 1 month and 2 to 4 months since receipt of the last dose of vaccine was estimated using logistic regression. The number of months since receipt of the last dose was calculated as the difference between the month and year of the test and the month and year of the last vaccine dose. For doses received in the month or month prior to test enrollment, people were asked if the most recent dose was received at least 2 weeks before the test date, and testing of people with less 2 weeks between the date of the last dose and the date of the test were excluded. Models were adjusted for calendar day of testing, age group, gender, race, ethnic group, testing site location (the Department of Health and Human Services region where the test was performed), the Social Vulnerability Index of the US Census Tract containing the test site, and the number of underlying chronic conditions (Tables S1 and S2 in the Supplementary Appendix).

Efficacy of four vaccination regimens against symptomatic infection with the Omicron variant in adults.

Vaccine efficacy was assessed in adults 18 years of age or older who were tested in the Increasing Community Access to Testing platform during the period of January 2 to March 23, 2022. Vaccine efficacy (calculated as [1−the odds ratio]×100) of each of the four regimens, compared to no vaccination, against symptomatic infection with severe acute respiratory syndrome coronavirus 2 omicron variant was estimated using logistic regression. Regression models were fitted for the number of days between the start of the analysis period and the date of the test (as a continuous variable with linear and quadratic terms), age group (18 to 24, 25-34, 35-44, 45-54, 55-64, and ≥ 65), gender, race, ethnic group, testing site location (the Department of Health and Human Services region where the test was performed), Social Vulnerability Index of the U.S. Census Tract containing the test site (dichotomized from 0 to

The vaccine efficacy of the Ad26.COV2.S regimen, compared to no vaccination, against symptomatic infection was 17.8% (95% confidence interval [CI], 4.3 to 29.5) during the period 14 days to 1 month since receipt of the last dose and 8.4% (95% CI, 1.5 to 14.8) during the period 2 to 4 months since receipt of the last dose. The corresponding values ​​for the Ad26.COV2.S/Ad26.COV2.S diet were 27.9% (95% CI, 18.3 to 36.5) and 29.2% (95% CI, 23. 1 to 34.8); for the Ad26.COV2.S/mRNA diet, 61.3% (95% CI, 58.4 to 64.0) and 54.3% (95% CI, 52.2 to 56.3); and for the mRNA/mRNA/mRNA diet, 68.9% (95% CI, 68.3 to 69.5) and 62.8% (95% CI, 62.2 to 63.4) (Figure 1).

Our results show that all regimens that included a booster dose, compared to no vaccination, provided protection against symptomatic infection with omicron (95% confidence intervals did not include 0), although vaccine efficacy was highest for regimens that included a booster dose. of an mRNA vaccine and was lowest for the homologous Ad26.COV2.S/Ad26.COV2.S regimen. The vaccine efficacy of the three-dose mRNA regimen and the Ad26.COV2.S/mRNA regimen was lower during the 2-4 month period since receiving the booster dose than during the 14-day period after receiving the booster dose. 1 month since receiving the booster dose; for the Ad26.COV2.S/Ad26.COV2.S diet, the 95% confidence intervals of the estimates for the two periods overlapped, but the sample sizes were smaller and the confidence intervals wider than for the others boosted diets. The limitations of our study have been described previously5 and include residual or unmeasured confounding related to unmeasured differences by vaccination status and test-seeking behavior. Nevertheless, the results of this study suggest that a single booster dose of a Covid-19 mRNA vaccine in individuals who received a primary vaccination with a single dose of Ad26.COV2.S provided protection close to that of the three-dose mRNA regimen and support the current recommendation of a booster dose of the mRNA vaccine at least 2 months after the primary vaccination with a single dose of Ad26.COV2.S or at least 4 months after a booster dose of Ad26.COV2.S.

Emma K. Accorsi, Ph.D.
Amadea Britton, MD
Nong Shang, Ph.D.
Katherine E. Fleming-Dutra, MD
Ruth Link-Gelles, Ph.D.
Zachary R. Smith, MA
Gordana Derado, Ph.D.
Joseph Miller, Ph.D.
Stephanie J. Schrag, D.Phil.
Jennifer R. Verani, MD
Centers for Disease Control and Prevention, Atlanta, GA
[email protected]

Supported by the CDC. Funding for the Increasing Community Access to Testing platform was provided by the Department of Health and Social Services.

The disclosure forms provided by the authors are available with the full text of this letter on NEJM.org.

The opinions expressed in this letter are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention (CDC).

This article was published on May 25, 2022 on NEJM.org.

Drs. Schrag and Verani also contributed to this letter.

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  2. 2. Atmar RL, Lyke KE, Deming me, et al. Homologous and heterologous Covid-19 booster vaccinations. N English J med 2022;386:10461057.

  3. 3. Maire FB, Talisa VB, Sheikh O, Yendé S, AA buttocks. Effectiveness of homologous or heterologous Covid-19 boosters in veterans. N English J med 2022;386:13751377.

  4. 4. Centers for Control and Prevention of Disasters. COVID Data Tracker (https://covid.cdc.gov/covid-data-tracker/#datatracker-home).

  5. 5. Accorsi EK, British A, Fleming-Dutra KE, et al. Association between 3 doses of COVID-19 mRNA vaccine and symptomatic infection caused by SARS-CoV-2 omicron and delta variants. JAMA 2022;327:639651.

Sara H. Byrd