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Effectiveness of Booster Doses of Monovalent mRNA COVID-19 Vaccine Against Symptomatic Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Children, Adolescents, and Adults During Omicron Subvariant BA.2/BA.2.12.1 and BA.4/BA.5 Predominant Periods

Effectiveness of Booster Doses of Monovalent mRNA COVID-19 Vaccine Against Symptomatic Severe... Open Forum Infectious Diseases MAJOR ARTICLE Effectiveness of Booster Doses of Monovalent mRNA COVID-19 Vaccine Against Symptomatic Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Children, Adolescents, and Adults During Omicron Subvariant BA.2/BA.2.12.1 and BA.4/BA.5 Predominant Periods 1,2, 1 3 1 1, 4 5,6 Allison Avrich Ciesla, Ryan E. Wiegand, Zachary R. Smith, Amadea Britton, Katherine E. Fleming-Dutra, Joseph Miller, Emma K. Accorsi, 5,7 5 5 1,a 1,7,a, Jennifer R. Verani, Nong Shang, Gordana Derado, Tamara Pilishvili, and Ruth Link-Gelles 1 2 3 National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA, Eagle Health Analytics, San Antonio, Texas, USA, Division of Research and Methodology, National Center for Health Statistics, Centers for Disease Control and Prevention, Hyattsville, Maryland, USA, Center for Preparedness and Response, Centers for Disease Control and Prevention, Atlanta, Georgia, USA, Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, 6 7 Atlanta, Georgia, USA, Epidemic Intelligence Service, Centers for Disease Control and Prevention, Atlanta, Georgia, USA, and US Public Health Service Commissioned Corps, Rockville, Maryland, USA Background. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) BA.2/BA.2.12.1 and BA.4/BA.5 subvariants have mutations associated with increased capacity to evade immunity when compared with prior variants. We evaluated mRNA monovalent booster dose effectiveness among persons ≥5 years old during BA.2/BA.2.12.1 and BA.4/BA.5 predominance. Methods. A test-negative, case-control analysis included data from 12 148 pharmacy SARS-CoV-2 testing sites nationwide for persons aged ≥5 years with ≥1 coronavirus disease-2019 (COVID-19)-like symptoms and a SARS-CoV-2 nucleic acid amplification test from April 2 to August 31, 2022. Relative vaccine effectiveness (rVE) was estimated comparing 3 doses of COVID-19 mRNA monovalent vaccine to 2 doses; for tests among persons ≥50 years, rVE estimates also compared 4 doses to 3 doses (≥4 months since third dose). Results. A total of 760 986 test-positive cases and 817 876 test-negative controls were included. Among individuals ≥12 years, rVE of 3 versus 2 doses ranged by age group from 45% to 74% at 1-month post vaccination and waned to 0% by 5–7 months post vaccination during the BA.4/BA.5 period. Adults aged ≥50 years (fourth dose eligible) who received 4 doses were less likely to have symptomatic SARS-CoV-2 infection compared with those with 3 doses; this rVE remained >0% through at least 3 months since last dose. For those aged ≥65 years, rVE of 4 versus 3 doses 1-month post vaccination was higher during BA.2/BA.2.12.1 (rVE = 49%; 95% confidence interval [CI], 43%– 53%) than BA.4/BA.5 (rVE = 40%; 95% CI, 36%–44%). In 50- to 64-year-olds, rVE estimates were similar. Conclusions. Monovalent mRNA booster doses provided additional protection against symptomatic SARS-CoV-2 infection during BA.2/BA.2.12.1 and BA.4/BA.5 subvariant circulation, but protection waned over time. Keywords. COVID-19; infection; monovalent boosters; SARS-CoV-2. In the United States, a monovalent coronavirus disease-2019 adults ≥65 years old (September 23, 2021), adults 18–64 (COVID-19) mRNA vaccine booster (third dose) was recom- (November 21, 2021), young adults 16–17 (December 9, mended by the Advisory Committee on Immunization 2021), and adolescents 12–15 (January 5, 2022) [1]. To address Practices at least 5 months after the last primary dose for older waning from this first booster dose, on March 29, 2022 the US Food and Drug Administration (FDA) authorized a second booster (fourth dose) of monovalent vaccine to be given at least Received 03 March 2023; editorial decision 03 April 2023; accepted 11 April 2023; published online 13 April 2023 4 months after receipt of a third dose for immunocompetent T.P. and R. L.-G. contributed equally to this work. adults aged ≥50 years, who are at increased risk of severe Correspondence: Allison Avrich Ciesla, PhD, Centers for Disease Control and Prevention, 1600 Clifton Road NE, MS H24-5, Atlanta, GA 30329 (ton4@cdc.gov); Ruth Link-Gelles, PhD, COVID-19. On May 19, 2022, a first booster (third dose) of a Centers for Disease Control and Prevention, 1600 Clifton Road NE, MS H24-5, Atlanta, GA monovalent vaccine was recommended for children aged 5–11 30329 (hzt7@cdc.gov). Open Forum Infectious Diseases years. Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023. Observational studies have demonstrated effectiveness of This work is written by (a) US Government employee(s) and is in the public domain in the US. https://doi.org/10.1093/ofid/ofad187 monovalent COVID-19 vaccine booster doses against the severe mRNA Boosters During BA.2 and BA.4/BA.5 • OFID • 1 acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta During BA.2/BA.2.12.1 predominance, all 4 pharmacy variant and Omicron BA.1 subvariant for a variety of outcomes chains with data were included in the analysis. During BA.4/ and populations [2–11]. However, Omicron BA.2/BA.2.12.1 BA.5 predominance, 1 pharmacy chain no longer contributed subvariants accounted for ≥75% of sequenced isolates in the data, whereas 2 pharmacy chains (1 new and 1 old comprising United States by April 11, 2022. The BA.2/BA.2.12.1 and of only 0.2% of the total tests during this period) began using a BA.4/BA.5 subvariants have additional mutations associated test registration form that gathered vaccination history differ- with increased capacity to evade neutralizing antibodies gener- ently, leaving this analysis with 2 chains with complete data ated in response to monovalent booster doses or BA.1 infection, during this period. Self-reported information was collected suggesting monovalent vaccines may be less effective in pre- from individuals registering for testing online, including vacci- venting infection against these subvariants [12–15]. nation history, gender, race, ethnicity, age, state of residence, To address waning monovalent vaccine effectiveness (VE) in symptom status, prior SARS-CoV-2 infections, and underlying the setting of Omicron variants, on September 1, 2022, the FDA conditions. Severe acute respiratory syndrome coronavirus 2 authorized bivalent COVID-19 mRNA vaccines for any per- NAAT date of collection, assay type, and results were reported sons who have completed a primary series, regardless of num- directly from testing sites. For detailed information on how vac- ber of doses, at least 2 months prior. Monitoring of monovalent cination history was collected, see Supplementary Information COVID-19 VE against SARS-CoV-2 infection during periods (Vaccination History Ascertainment). of BA.2/BA.2.12.1 and BA.4/BA.5 subvariant predominance is crucial to inform vaccine policy by setting a baseline to un- Study Design derstand how well newly authorized bivalent vaccines may A test-negative design was used to evaluate relative and abso- work. We analyzed data from a national, pharmacy-based lute effectiveness against symptomatic SARS-CoV-2 infection SARS-CoV-2 testing program, Increasing Community Access of 1 booster (3 doses) compared to 2 doses or unvaccinated, to Testing (ICATT) [16], to estimate age group-specific effec- and effectiveness of 2 booster doses (4 doses) compared to 3 tiveness of 1 or 2 monovalent mRNA vaccine booster doses doses or unvaccinated. At registration, persons were asked among persons aged ≥5 years during periods of Omicron whether they had an immunocompromising condition using BA.2/BA.2.12.1 and BA.4/BA.5 subvariant predominance. the following examples: immunocompromising medications, solid organ or blood stem cell transplant, human immunodefi - ciency virus (HIV), or other immunocompromising condi- METHODS tions. The respondents were excluded if they reported an Data Source immunocompromising condition. The unit of analysis was ICATT is a Department of Health and Human Services program tests: among individuals with ≥1 COVID-19-like illness symp- that contracts with pharmacy chains and laboratories to provide toms, cases were defined by a positive NAAT result and con- no-cost, drive-through SARS-CoV-2 testing at selected sites na- trols were defined by a negative NAAT result. Individuals tionwide [7–9, 16]. The ICATT program seeks to address reporting any prior SARS-CoV-2 infection were excluded COVID-19 health disparities by selecting SARS-CoV-2 testing from analysis. sites located in (1) racially and ethnically diverse communities, small towns, and rural communities as assessed using Rural- Exposures Urban Commuting Area (RUCA) codes [17] and (2) areas The main exposures were receipt of 1 booster dose for individ- with moderate to high social vulnerability based on Centers uals aged 5 to 49 years and receipt of 1 or 2 booster doses for in- for Disease Control and Prevention (CDC)/Agency for Toxic dividuals aged 50 years and older, with last dose received ≥2 Substances and Disease Registry (ATSDR) 2018 Social weeks before test dates. During the analysis time frame, Vulnerability Index (SVI) data [18, 19]. bivalent mRNA vaccines had not yet been authorized; thus, ICATT data were analyzed from SARS-CoV-2 nucleic acid reported mRNA vaccine doses were assumed to be monovalent. amplification tests (NAATs) performed during BA.2/ Individuals were excluded if they (1) were aged 5 to 49 years and BA.2.12.1 (April 2–June 11, 2022) and BA.4/BA.5 (July 2– received >3 doses or were aged ≥50 years and received >4 doses, August 31, 2022) Omicron subvariant predominance, based (2) received a booster dose earlier (<5 months) than the recom- on when each subvariant accounted for ≥75% of all sequenced mended interval, (3) received any doses of a non-mRNA vaccine, isolates in the United States [20]. Because neither set of subvar- (4) received only 1 dose of vaccine, or (5) were missing vaccina- iants accounted for at least 75% of sequenced isolates between tion information or covariables of interest. June 12 and July 1, 2022, tests performed during this period For estimating relative VE (rVE) comparing 3 versus 2 doses, were excluded from analyses. Analytic start dates for age groups the reference group consisted of individuals who had received 2 varied based on vaccine product and timing of product autho- doses and were eligible for a third dose (ie, ≥5 months since rization (Supplementary Table 1). second dose). Similarly, for estimating rVE comparing 4 versus 2 • OFID • Ciesla et al 3 doses, the reference group consisted of individuals who had last dose was calculated as the interval between month of test- received 3 doses and were eligible for a fourth dose (ie, ≥4 ing and month of the last dose. Because the interval of 2 weeks months since third dose). For absolute VE (aVE) analyses, was required between the last dose and testing date, and only the reference group for all exposure categories were unvacci- month of vaccination was available for 2 pharmacy chains, nated individuals who had not received any doses of we designated intervals as follows: 0 month (ie, testing and vac- COVID-19 vaccine. Absolute VE estimates are presented for cination in the same month), 14 to 30 days; 1 month, 14 to 60 time frames at which the next dose was recommended (ie, 5 days; 2 months, 30 to 90 days; 3 months, 60 to 120 days, and so or 4 months after the last dose and eligible for a first or second on (assuming 30-day month intervals). For example, person A booster). was vaccinated on June 1, 2022 and tested on July 31, 2022 (month interval, 1; days, 60). Person B was vaccinated on Statistical Analysis June 14, 2022 and tested on August 15, 2022 (month interval, For rVE, we estimated associations between SARS-CoV-2 in- 2; days, 60). A simulation study found VE results utilizing fection and prior mRNA vaccination status using multivariable months since vaccination was similar to using days since vacci- logistic regression. In secondary analyses, we estimated aVE by nation [9]. Statistical analyses were performed in R (version comparing odds of vaccination with 2, 3, or 4 doses of an 4.1.2; R Foundation for Statistical Computing, Vienna, mRNA vaccine versus being unvaccinated among cases and Austria). test-negative controls using multivariable logistic regression. All VE estimates were expressed as a percentage and calculated Patient Consent Statement from odds ratios (ORs) by the formula (1 − OR) × 100. This activity was reviewed by the CDC and was conducted con- Models were adjusted for calendar day of test (modeled as a sistent with applicable federal law and CDC policy (see 45 continuous linear variable), age, gender, race, ethnicity, phar- C.F.R. part 46; 21 C.F.R. part 56; 42 U.S.C. §241(d), 5 U.S.C. macy site census tract SVI, underlying conditions (presence §552a, 44 U.S.C. §3501 et seq). It was determined to be public vs absence) (list of conditions in Supplementary Table 2), state health surveillance and was not submitted for institutional re- of residence, pharmacy chain, and 7-day average of cases per view board approval and informed consent was not needed. 100 000 by site zip code (local incidence: modeled as a contin- uous linear variable). Both calendar day of test and local inci- RESULTS dence were evaluated for presence of a nonlinear relationship A total of 1 578 862 tests for SARS-CoV-2 from 12 148 sites by plotting the quartiles of each continuous variable against across 49 states, Puerto Rico, and Washington, DC met inclu- the probability of the log odds of having a positive NAAT. sion criteria (Figure 1), including 760 986 cases (395 196 during Calendar day of test had a continuous linear relationship, Omicron BA.2/BA.2.12.1 and 365 790 Omicron BA.4/BA.5 pe- whereas local incidence had a slight logarithmic relationship riods) and 817 876 test-negative controls (496 407 Omicron with the outcome. Sensitivity analyses including the log of local BA.2/BA.2.12.1 and 321 469 Omicron BA.4/BA.5) (Table 1). incidence produced no differences in the main effect. When Sixty-three percent of tests were laboratory-based NAAT race or ethnicity were not reported, they were classified as “un- (37% with rapid NAAT). Approximately 62% of tests included known” race/ethnicity and included as a separate category in were from persons aged 16–49 years, 923 007 were female analyses (Supplementary Table 2). (58%), 873 969 were White (55%), and 324 185 were Adjusted VE estimates were stratified by age group with Hispanic/Latino (21%). Among tests included in analyses, month since last vaccine dose included as a categorical variable 41% were from persons who reported receiving 3 doses (range, based on analytic start and stop dates for each age group 3% of 5-11 age group to 49% of ≥65 age group) and 34% from (Supplementary Table 1). Age group-specific models estimated persons who received 2 doses (range, 19% of ≥65 age group to rVE for 4 versus 3 doses (50–64 years, ≥65 years) and for 3 ver- 45% of 12–15 age group) of an mRNA vaccine. The proportion sus 2 doses (12–15 years, 16–49 years, 50–64 years, ≥65 years). of the study population reporting 1 of more underlying condi- For children ages 5 to 11 years, rVE estimates for 3 versus 2 dos- tions ranged from 4% (5–11 years) to 52% (≥65 years). Age dis- es were calculated overall, rather than by month since third tributions and frequencies of underlying conditions by age dose, due to the short time frame when the booster was recom- group are reported in Supplementary Table 2. mended. Absolute VE 2 doses versus unvaccinated (all age groups), 3 doses versus unvaccinated (age groups ≥12 years), and 4 doses versus unvaccinated (50–64 years, ≥65 years) Relative Vaccine Effectiveness were also estimated. For children aged 5–11 years, rVE of 3 versus 2 doses of mRNA Two of the 4 pharmacy chains collected month and year of vaccine against infection was 77% (95% confidence interval vaccination (without day) during the study period. Two phar- [CI], 54%–88%; maximum time since last dose, <1 month) macy chains collected exact day of vaccination. Months since during BA.2/BA.2.12.1 predominance and 56% (95% CI, mRNA Boosters During BA.2 and BA.4/BA.5 • OFID • 3 Figure 1. Inclusion criteria for analysis of association of booster doses of an mRNA COVID-19 vaccine with symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children, adolescents, and adults during BA.2/BA.2.12.1 (April 2, 2022–June 11, 2022) and BA.4/BA.5 (July 2, 2022–August 31, 2022) predominant periods. EUA, Emergency Use Authorization; ICATT, Increasing Community Access to Testing; NAAT, nucleic acid amplification test; y, years. 50%–60%; maximum time, 3.5 months) during BA.4/BA.5 pre- during BA.4/BA.5 (95% CI, 5%–19%) (Figure 2; dominance (Supplementary Table 3). Supplementary Table 3). Estimates of rVE for 3 versus 2 doses of mRNA vaccine for Relative VE of 3 versus 2 doses among adults ≥65 years at 1 children aged 12–15 years at 1 month post third dose was month after receipt of third dose was 45% (95% CI, 35%– 74% (95% CI, 65%–81%) during BA.2/BA.2.12.1 and 62% 54%) during BA.2/BA.2.12.1 and 50% (95% CI, 37%–61%) dur- (95% CI, 51%–70%) during BA.4/BA.5. At 5 months ing BA.4/BA.5. By 5 months post third dose receipt, rVE de- post third dose receipt, VE was 38% (95% CI, 26%–47%) during clined to 11% (95% CI, 6%–15%) during BA.2/BA.2.12.1 and BA.2/BA.2.12.1 and 11% (95% CI, −8% to 26%) during BA.4/ 13% (95% CI, 0%–24%) during BA.4/BA.5 (Figure 2; BA.5 (Figure 2; Supplementary Table 3). Supplementary Table 3). Adults aged 16–49 years at 1 month post third dose receipt At 1 month after receipt of a fourth dose, rVE for 4 versus 3 dos- had a rVE for 3 versus 2 doses of 58% (95% CI, 55%–61%) dur- es among adults aged 50–64 years was 48% (95% CI, 44%–51%) ing BA.2/BA.2.12.1 and 56% (95% CI, 52%–60%) during BA.4/ during BA.2/BA.2.12.1 and 45% (95% CI, 41%–48%) during BA.5. Relative VE was lower by 5 months after third dose re- BA.4/BA.5. In the third month since receipt of the fourth dose, ceipt for BA.2/BA.2.12.1 predominance (VE, 14%; 95% CI, rVE was 74% (95% CI, 54%–85%) during BA.2/BA.2.12.1 and 13%–16%) and BA.4/BA.5 predominance (VE, 13%; 95% CI, 38% (95% CI, 33%–41%) during BA.4/BA.5. Among adults ages 9%–17%) (Figure 2; Supplementary Table 3). ≥65 years at 1 month after receipt of a fourth dose, rVE for 4 ver- rVE for 3 versus 2 doses among those aged 50–64 years at 1 sus 3 doses was 49% (95% CI, 46%–51%) during BA.2/BA.2.12.1 month after third dose receipt was 60% (95% CI, 54%–65%) and 40% (95% CI, 36%–44%) during BA.4/BA.5. In the third during BA.2/BA.2.12.1 and 57% (95% CI, 50%–64%) during month since receipt of the fourth dose, rVE was 58% (95% CI, BA.4/BA.5. At 5 months post third dose receipt, rVE decreased 47%–66%) during BA.2/BA.2.12.1 and 33% (95% CI, 30%–36%) to 11% during BA.2/BA.2.12.1 (95% CI, 8%–13%) and 12% during BA.4/BA.5 (Figure 3; Supplementary Table 3). 4 • OFID • Ciesla et al mRNA Boosters During BA.2 and BA.4/BA.5 • OFID • 5 a b Table 1. Distribution of Characteristics for Symptomatic SARS-CoV-2 Cases and Symptomatic Test-Negative Controls Without Self-Reported Prior SARS-CoV-2 Infection During BA.2/BA.2.12.1 and BA.4/BA.5 Predominant Periods by Age Group Cases (SARS-CoV-2 Positive) Controls (SARS-CoV-2 Negative) No. (%) No. (%) Doses of mRNA COVID-19 Vaccine No. (%) … … … Characteristic BA.2/BA.2.12.1 BA.4/BA.5 BA.2/BA.2.12.1 BA.4/BA.5 Unvaccinated 2 3 4 Overall 5–11 Years Old Vaccination History … … … … … … … … … Unvaccinated 8335 (53) 8298 (64) 20 307 (52) 11 682 (57) 48 622 (100) 0 (0) 0 (0) 0 (NA) 48 622 (55) 2 Doses 7403 (47) 4209 (32) 18 811 (48) 7119 (34) 0 (0) 37 542 (100) 0 (0) 0 (NA) 37 542 (42) 3 Doses 12 (0.08) 505 (4) 90 (0.2) 1859 (9) 0 (0) 0 (0) 2466 (100) 0 (NA) 2466 (3) 4 Doses 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (NA) 0 (0) SARS-CoV-2 Positive … … … … … … … … … BA.2/BA2.12.1 15 750 (100) 0 (0) 0 (0) 0 (0) 8335 (17) 7403 (20) 12 (0.5) 0 (NA) 15 750 (18) BA.4/BA.5 0 (0) 13 012 (100) 0 (0) 0 (0) 8298 (17) 4209 (11) 505 (20) 0 (NA) 13 012 (15) SARS-CoV-2 Negative … … … … … … … … … BA.2/BA.2.12.1 0 (0) 0 (0) 39 208 (100) 0 (0) 20 307 (42) 18 811 (50) 90 (4) 0 (NA) 39 208 (44) BA.4/BA.5 0 (0) 0 (0) 0 (0) 20 660 (100) 11 682 (24) 7119 (19) 1859 (75) 0 (NA) 20 660 (23) SARS-CoV-2 Test Type, NAAT Only … … … … … … … … … Rapid 5849 (37) 5150 (40) 17 761 (45) 9604 (46) 22 165 (46) 15 315 (41) 884 (36) 0 (NA) 38 364 (43) Laboratory-based 9901 (63) 7862 (60) 21 447 (55) 11 056 (54) 26 457 (54) 22 227 (59) 1582 (64) 0 (NA) 50 266 (57) Underlying chronic conditions , any (%) 524 (3) 492 (4) 1320 (3) 804 (4) 1630 (3) 1397 (4) 113 (5) 0 (NA) 3140 (4) 12–15 Years Old Vaccination History … … … … … … … … … Unvaccinated 3545 (33) 3566 (40) 6383 (34) 4114 (33) 17 608 (100) 0 (0) 0 (0) 0 (NA) 17 608 (34) 2 Doses 5343 (49) 3762 (42) 8433 (44) 5409 (44) 0 (0) 22 947 (100) 0 (0) 0 (NA) 22 947 (45) 3 Doses 1926 (18) 1581 (18) 4187 (22) 2853 (23) 0 (0) 0 (0) 10 547 (100) 0 (NA) 10 547 (21) 4 Doses 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (NA) 0 (0) SARS-CoV-2 Positive … … … … … … … … … BA.2/BA2.12.1 10 814 (100) 0 (0) 0 (0) 0 (0) 3545 (20) 5343 (23) 1926 (18) 0 (NA) 10 814 (21) BA.4/BA.5 0 (0) 8909 (100) 0 (0) 0 (0) 3566 (20) 3762 (16) 1581 (15) 0 (NA) 8909 (17) SARS-CoV-2 Negative … … … … … … … … … BA.2/BA.2.12.1 0 (0) 0 (0) 19 003 (100) 0 (0) 6383 (36) 8433 (37) 4187 (40) 0 (NA) 19 003 (37) BA.4/BA.5 0 (0) 0 (0) 0 (0) 12 376 (100) 4114 (23) 5409 (24) 2853 (27) 0 (NA) 12 376 (24) SARS-CoV-2 Test Type, NAAT Only … … … … … … … … … Rapid 4095 (38) 3395 (38) 8644 (45) 5948 (48) 7904 (45) 10 487 (46) 3691 (35) 0 (NA) 22 082 (43) Laboratory-based 6719 (62) 5514 (62) 10 359 (55) 6428 (52) 9704 (55) 12 460 (54) 6856 (65) 0 (NA) 29 020 (57) Underlying chronic conditions , any (%) 504 (5) 492 (6) 1068 (6) 760 (6) 904 (5) 1271 (6) 649 (6) 0 (NA) 2824 (6) 16–49 Years Old Vaccination History … … … … … … … … … Unvaccinated 47 383 (19) 55 070 (24) 67 460 (22) 47 171 (24) 217 084 (100) 0 (0) 0 (0) 0 (NA) 217 084 (22) 2 Doses 91 712 (37) 89 960 (39) 98 626 (33) 74 942 (38) 0 (0) 355 240 (100) 0 (0) 0 (NA) 355 240 (36) 6 • OFID • Ciesla et al Table 1. Continued Cases (SARS-CoV-2 Positive) Controls (SARS-CoV-2 Negative) No. (%) No. (%) Doses of mRNA COVID-19 Vaccine No. (%) … … … Characteristic BA.2/BA.2.12.1 BA.4/BA.5 BA.2/BA.2.12.1 BA.4/BA.5 Unvaccinated 2 3 4 Overall 3 Doses 106 149 (43) 84 893 (37) 135 206 (45) 76 508 (39) 0 (0) 0 (0) 402 756 (100) 0 (NA) 402 756 (41) 4 Doses 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (NA) 0 (0) SARS-CoV-2 Positive … … … … … … … … … BA.2/BA2.12.1 245 244 (100) 0 (0) 0 (0) 0 (0) 47 383 (22) 91 712 (26) 106 149 (26) 0 (NA) 245 244 (25) BA.4/BA.5 0 (0) 229 923 (100) 0 (0) 0 (0) 55 070 (25) 89 960 (25) 84 893 (21) 0 (NA) 229 923 (24) SARS-CoV-2 Negative … … … … … … … … … BA.2/BA.2.12.1 0 (0) 0 (0) 301 292 (100) 0 (0) 67 460 (31) 98 626 (28) 135 206 (34) 0 (NA) 301 292 (31) BA.4/BA.5 0 (0) 0 (0) 0 (0) 198 621 (100) 47 171 (22) 74 942 (21) 76 508 (19) 0 (NA) 198 621 (20) SARS-CoV-2 Test Type, NAAT Only … … … … … … … … … Rapid 89 303 (36) 83 912 (36) 114 487 (38) 80 574 (41) 90 379 (42) 149 267 (42) 128 630 (32) 0 (NA) 368 276 (38) Laboratory-based 155 941 (64) 146 011 (64) 186 805 (62) 118 047 (59) 126 705 (58) 205 973 (58) 274 126 (68) 0 (NA) 606 804 (62) Underlying chronic conditions , any (%) 41 453 (17) 39 310 (17) 56 114 (19) 36 666 (18) 34 756 (16) 61 899 (17) 76 888 (19) 0 (NA) 173 543 (18) 50–64 Years Old Vaccination History … … … … … … … … … Unvaccinated 10 376 (13) 9526 (13) 11 193 (14) 6906 (13) 38 001 (100) 0 (0) 0 (0) 0 (0) 38 001 (13) 2 Doses 25 633 (33) 25 415 (34) 22 712 (28) 17 681 (33) 0 (0) 91 441 (100) 0 (0) 0 (0) 91 441 (32) 3 Doses 40 378 (51) 32 282 (44) 42 960 (53) 21 795 (40) 0 (0) 0 (0) 137 415 (100) 0 (0) 137 415 (48) 4 Doses 2466 (3) 6712 (9) 3876 (5) 7851 (14) 0 (0) 0 (0) 0 (0) 20 905 (100) 20 905 (7) SARS-CoV-2 Positive … … … … … … … … … BA.2/BA2.12.1 78 853 (100) 0 (0) 0 (0) 0 (0) 10 376 (27) 25 633 (28) 40 378 (29) 2466 (12) 78 853 (27) BA.4/BA.5 0 (0) 73 935 (100) 0 (0) 0 (0) 9526 (25) 25 415 (28) 32 282 (23) 6712 (32) 73 935 (26) SARS-CoV-2 Negative … … … … … … … … … BA.2/BA.2.12.1 0 (0) 0 (0) 80 741 (100) 0 (0) 11 193 (29) 22 712 (25) 42 960 (31) 3876 (19) 80 741 (28) BA.4/BA.5 0 (0) 0 (0) 0 (0) 54 233 (100) 6906 (18) 17 681 (19) 21 795 (16) 7851 (38) 54 233 (19) SARS-CoV-2 Test Type, NAAT Only … … … … … … … … … Rapid 30 363 (39) 26 123 (35) 31 372 (39) 20 950 (39) 15 489 (41) 38 267 (42) 48 871 (36) 6181 (30) 108 808 (38) Laboratory-based 48 490 (61) 47 812 (65) 49 369 (61) 33 283 (61) 22 512 (59) 53 174 (58) 88 544 (64) 14 724 (70) 178 954 (62) Underlying chronic conditions , any (%) 28 686 (36) 28 448 (38) 31 303 (39) 21 748 (40) 13 402 (35) 35 344 (39) 52 916 (39) 8523 (41) 110 185 (38) ≥65 Years Old Vaccination History … … … … … … … … … Unvaccinated 3661 (8) 2948 (7) 4560 (8) 2508 (7) 13 677 (100) 0 (0) 0 (0) 0 (0) 13 677 (8) 2 Doses 8723 (20) 8805 (22) 8971 (16) 6704 (19) 0 (0) 33 203 (100) 0 (0) 0 (0) 33 203 (19) 3 Doses 26 181 (59) 16 527 (41) 31 790 (57) 12 247 (34) 0 (0) 0 (0) 86 745 (100) 0 (0) 86 745 (49) 4 Doses 5970 (13) 11 731 (29) 10 842 (19) 14 120 (40) 0 (0) 0 (0) 0 (0) 42 663 (100) 42 663 (24) SARS-CoV-2 Positive … … … … … … … … … BA.2/BA2.12.1 44 535 (100) 0 (0) 0 (0) 0 (0) 3661 (27) 8723 (26) 26 181 (30) 5970 (14) 44 535 (25) BA.4/BA.5 0 (0) 40 011 (100) 0 (0) 0 (0) 2948 (22) 8805 (27) 16 527 (19) 11 731 (27) 40 011 (23) Absolute Vaccine Effectiveness Estimates of aVE for 2, 3, and 4 doses compared to no doses (unvaccinated) during BA.2/BA.2.12.1 and BA.4/BA.5 pre- dominance were similar across all age groups and declined by time since last dose receipt (Supplementary Figures 1–3). In aVE models, 2 doses were no longer effective by 6 months after receipt of the second dose for all age groups and during both subvariant periods except for children aged 5–11 years where 2 doses remained effective throughout the BA.2/BA.2.12.1 study period. Three doses were no longer effective by 6 months after receipt of the third dose for those ≥16 years. DISCUSSION In this analysis of national pharmacy testing data, monovalent mRNA boosters provided additional protection against symp- tomatic SARS-CoV-2 infection among adults, adolescents, and children across BA.2/BA.2.12.1 and BA.4/BA.5 predominant periods. During BA.4/BA.5, protection among adults ≥50 years declined moderately and remained above zero 4 months after receipt of the second booster dose. Among adolescents 12–15 years old, the first booster (dose 3) was no longer effective by 5 months after receipt, and by 6 months after receipt among those 16–49 years old. In March 2022, the FDA authorized a fourth monovalent vaccine dose for all adults aged 50 years and older 4 months af- ter receiving their third dose. As of September 21, 2022, a mi- nority of adults ≥50 years (35.5%) and ≥65 years (42.8%) had received a second booster (fourth dose) [21]. However, the cur- rent study demonstrates added benefit of the fourth dose against infection, particularly 3–5 months after vaccination. These results are consistent with immunogenicity studies dem- onstrating an increase in antibodies from a fourth dose after al- most a 10-fold antibody decrease due to waning after the third dose, and studies evaluating effectiveness of 4 versus 3 doses of mRNA vaccine [22–26]. Relative VE of a third mRNA dose over a second waned with time after receipt of the third dose. Similar waning was seen during both Omicron periods in this analysis. During pre-Omicron, waning of rVE for 3 versus 2 doses has been ob- served among adults against infection but not against more se- vere outcomes [27]. Previous analyses from this ICATT platform have noted waning of aVE against infection among adolescents aged 12–15 years [9] and adults [8] during the early Omicron period; our results suggest continued waning oc- curred during this study period after receipt of 3 doses of an mRNA vaccine. A similar magnitude of waning was observed across all age groups. To contextualize interpretation of our primary analysis of rVE, we evaluated aVE for 4, 3, and 2 doses versus no doses, and we found similar patterns of waning after receipt of 2 or 3 doses. Absolute VE estimates for 2 and 3 doses at 5 months mRNA Boosters During BA.2 and BA.4/BA.5 • OFID • 7 Table 1. Continued Cases (SARS-CoV-2 Positive) Controls (SARS-CoV-2 Negative) No. (%) No. (%) Doses of mRNA COVID-19 Vaccine No. (%) … … … Characteristic BA.2/BA.2.12.1 BA.4/BA.5 BA.2/BA.2.12.1 BA.4/BA.5 Unvaccinated 2 3 4 Overall SARS-CoV-2 Negative … … … … … … … … … BA.2/BA.2.12.1 0 (0) 0 (0) 56 163 (100) 0 (0) 4560 (33) 8971 (27) 31 790 (37) 10 842 (25) 56 163 (32) BA.4/BA.5 0 (0) 0 (0) 0 (0) 35 579 (100) 2508 (18) 6704 (20) 12 247 (14) 14 120 (33) 35 579 (20) SARS-CoV-2 Test Type, NAAT Only … … … … … … … … … Rapid 18 896 (42) 14 612 (37) 22 846 (41) 13 433 (38) 6067 (44) 14 602 (44) 34 655 (40) 14 463 (34) 69 787 (40) Laboratory-based 25 639 (58) 25 399 (63) 33 317 (59) 22 146 (62) 7610 (56) 18 601 (56) 52 090 (60) 28 200 (66) 106 501 (60) Underlying chronic conditions , any (%) 22 528 (51) 21 051 (53) 28 937 (52) 19 349 (54) 5776 (42) 17 311 (52) 45 804 (53) 22 974 (54) 91 865 (52) Abbreviations: COVID-19, coronavirus disease 2019; NA, not applicable; NAAT, nucleic acid amplification test; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. BA.2/BA.2.12.1: April 2, 2022–June 11, 2022. BA.4/BA.5: July 2, 2022–August 31, 2022. Only month and year of receipt were reported for each vaccination dose from some participating pharmacies; therefore, the number of months between a vaccine dose and testing is a whole number calculated as the difference between the month and year of testing and the month and year of the vaccine dose. Persons reporting a non-mRNA vaccination were excluded from analyses. For doses received in the same month or the month before SARS-CoV-2 testing, an additional question was asked to specify whether the dose was received ≥2 weeks before testing, and only doses received ≥2 weeks before testing were included. Rapid NAAT was performed onsite on self-collected nasal swabs using ID Now (Abbott Diagnostics Scarborough Inc.) and Accula (Thermo Fisher Scientific). Laboratory-based NAAT was performed on self-collected nasal swabs at contracted laboratories using a variety of testing platforms. Underlying conditions included on the survey were as follows: heart conditions, high blood pressure, overweight or obesity, diabetes, current or former smoker, kidney failure or end-stage renal disease, cirrhosis of the liver, chronic lung disease (such as chronic obstructive pulmonary disease, moderate to severe asthma, cystic fibrosis, or pulmonary embolism). Figure 2. Adjusted mRNA COVID-19 relative vaccine effectiveness of 3 doses compared to 2 doses against symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during BA.2/BA.2.12.1 (April 2, 2022–June 11, 2022) and BA.4/BA.5 (July 2, 2022–August 31, 2022) periods by time since third dose receipt. Multivariable logistic regression models controlling for calendar day of test (continuous), age, gender, race, ethnicity, 2018 Centers for Disease Control and Prevention census tract social vulnerability index, underlying conditions (presence vs absence—included on the survey were heart conditions, high blood pressure, overweight or obesity, di- abetes, current or former smoker, kidney failure or end-stage renal disease, cirrhosis of the liver, chronic lung disease [such as chronic obstructive pulmonary disease, mod- erate to severe asthma, cystic fibrosis, or pulmonary embolism]), individual state of residence, pharmacy chain, and average cases per 100 000 by site zip code (over the last 7 days) were used to estimate vaccine effectiveness. Tests included in the reference group were from persons receiving 2 doses and eligible for a third dose (ie, if 5 months had passed since second dose). (A) Children aged 12–15 years. (B) Young adults aged 16–49 years. (C) Adults aged 50–64 years. (D) Adults aged 65 years and older. post receipt were zero (ie, no protection), indicating rVE likely in antibody levels and neutralizing activity [26] underscore the approximates aVE. Significantly negative rVE estimates ob- continued need for people of all ages to remain current with served among adults aged ≥50 years during BA.4/BA.5 pre- their COVID-19 vaccinations. Despite the emergence of new dominance 7–9 months post receipt of a third dose compared subvariants, mRNA vaccines continue to demonstrate at least to those with 2 doses and higher aVE by time since fourth short-term effectiveness against infection and longer term pro- dose may represent residual confounding, potentially due to tection against more severe outcomes. Recently approved underreported prior SARS-CoV-2 infection. COVID-19 bivalent mRNA vaccines, more closely matching A recent study by Petrie et al [25] reported similar findings currently circulating variants, appear to provide increased pro- with modest to high protection after the third dose (or first tection [32–34]. booster) compared to a primary series that waned to null by 6 months after receipt of the third dose. Petrie et al [25] found Limitations no significant VE after the second booster dose when compared There are several important limitations of this study. First, to a single booster dose, whereas an earlier study from Israel these data are from pharmacies selected based on RUCA codes confirmed similar VE to our study with a relative VE of 52% [17] and SVI [19] to better reach underserved communities; (95% CI, 49%–54%) in the first month after the fourth dose therefore, the population included may not be representative [28]. Other recent findings showing that 4 doses are effective of the general US population, or even geographic areas where against severe COVID-19 disease [29–31], and have an increase reporting pharmacy sites are located. Second, the population 8 • OFID • Ciesla et al Figure 3. Adjusted mRNA COVID-19 relative vaccine effectiveness of 4 doses compared to 3 doses against symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during BA.2/BA.2.12.1 (April 2, 2022–June 11, 2022) and BA.4/BA.5 (July 2, 2022–August 31, 2022) periods by time since fourth dose receipt. Multivariable logistic regression models controlling for calendar day of test (continuous), age, gender, race, ethnicity, 2018 Centers for Disease Control and Prevention census tract social vulnerability index, underlying conditions (presence vs absence—included on the survey were heart conditions, high blood pressure, overweight or obesity, di- abetes, current or former smoker, kidney failure or end-stage renal disease, cirrhosis of the liver, chronic lung disease [such as chronic obstructive pulmonary disease, mod- erate to severe asthma, cystic fibrosis, or pulmonary embolism]), individual state of residence, pharmacy chain, and average cases per 100 000 by site zip code (over the last 7 days) were used to estimate vaccine effectiveness. Tests included in the reference group were from persons receiving 3 doses and eligible for a fourth dose (ie, if 5 months had passed since third dose). (A) Adults aged 50–64 years. (B) Adults aged 65 years or older. included is based on persons accessing pharmacies for Our study highlights how VE against SARS-CoV-2 infection SARS-CoV-2 testing. Changes in individual testing practices changes over time, which can signal reduced effectiveness and increased use of home tests [35], by presence of symptoms against new variants, waning vaccine protection, or both. We or vaccination status, could introduce selection bias. Third, we found booster doses provide added protection against did not have information on community or household-level ex- SARS-CoV-2 infection among immunocompetent persons posures, individual prevention behaviors (eg, mask use), or ages 5 years and older during BA.2/BA.2.12.1 and BA.4/BA.5 other confounders [36]. Those who remain unvaccinated may predominance. However, protection waned in the months after be fundamentally different from vaccinated individuals. vaccination; although little to no waning was observed after the Fourth, vaccination status and prior infection were self- fourth dose in older adults, long-term follow up was not avail- reported and subject to recall bias; therefore, there is a potential able. Recently introduced bivalent COVID-19 mRNA vaccine for misclassification. As of June 2022, 58.7% of the US popula- doses have the potential to restore protection against circulating tion had infection-induced seroprevalence; however, only 21% new Omicron subvariants. Our study supports the need to stay (during BA.2/BA.2.12.1) and 31% (during BA.4/BA.5) of the up to date on recommended doses of COVID-19 vaccines. initial sample reported prior infection [37], indicating underre- Supplementary Data porting of prior infection. Given the poor characterization of Supplementary materials are available at Open Forum Infectious Diseases prior infection in this sample, the present study included online. Consisting of data provided by the authors to benefit the reader, the only individuals who indicated no prior infection. posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the correspond- ing author. CONCLUSIONS Acknowledgments Although the goal of the US COVID-19 vaccination program is We thank Stephanie J. Schrag (Centers for Disease Control and prevention of severe disease [38], VE against symptomatic in- Prevention [CDC]). fection can provide important insight to help understand Author contributions. AAC and REW had full access to the data used in the how vaccines are working in the real world, especially in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. AAC, RL-G, AB, KEF-D, JRV, TP, and REW contrib- context of emerging variants and before estimates against uted to concept and design. All authors contributed to acquisition, analysis, more severe outcomes are available. Continued monitoring of or interpretation of data. AAC, RL-G, TP, and REW drafted the manu- COVID-19 VE is crucial to inform and guide future vaccine script. All authors contributed to critical revision of the manuscript for im- policy decisions. portant intellectual content. AAC, NS, GD, and REW contributed to mRNA Boosters During BA.2 and BA.4/BA.5 • OFID • 9 18. Flanagan BE, Gregory EW, Hallisey EJ, Heitgerd JL, Lewis B. A social vulnerability statistical analysis. JM obtained funding. ZRS, AB, KEF-D, JM, JRV, TP, index for disaster management. J Homel Secur Emerg Manag 2011; 8:1–22. and RL-G contributed to administrative, technical, or material support. 19. U.S. Centers for Disease Control and Prevention. CDC/ATSDR Social JM, TP, RL-G, and REW supervised the work. Vulnerability Index (2018). Available at: https://www.atsdr.cdc.gov/placeandhe Disclaimer. The findings and conclusions in this report are those of the alth/svi/index.html. Accessed 19 October 2022. authors and do not necessarily represent the official position of the CDC. 20. Centers for Disease Control and Prevention. SARS-CoV-2 Variant Proportions. Financial support. Funding for the Increasing Community Access to Available at: https://data.cdc.gov/Laboratory-Surveillance/SARS-CoV-2-Varia Testing platform is provided by the US Department of Health and nt-Proportions/jr58-6ysp. Accessed 28 July 2022. Human Services. Funding for this analysis was provided by the CDC. 21. Centers for Disease Control and Prevention. COVID-19 Vaccinations in the Potential conflicts of interest. None reported. United States. Available at: https://covid.cdc.gov/covid-data-tracker/#vaccina tions_vacc-people-additional-dose-totalpop. Accessed 27 September 2022. Role of the funder/sponsor. 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Available Advisory Committee on Immunization Practices for the use of bivalent booster at: https://www.ers.usda.gov/data-products/rural-urban-commuting-area-codes. doses of COVID-19 vaccines—United States, October 2022. MMWR Morb aspx. Accessed 19 October 2022. Mortal Wkly Rep 2022; 71:1436–41. 10 • OFID • Ciesla et al http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Open Forum Infectious Diseases Oxford University Press

Effectiveness of Booster Doses of Monovalent mRNA COVID-19 Vaccine Against Symptomatic Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Children, Adolescents, and Adults During Omicron Subvariant BA.2/BA.2.12.1 and BA.4/BA.5 Predominant Periods

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Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.
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Open Forum Infectious Diseases MAJOR ARTICLE Effectiveness of Booster Doses of Monovalent mRNA COVID-19 Vaccine Against Symptomatic Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Children, Adolescents, and Adults During Omicron Subvariant BA.2/BA.2.12.1 and BA.4/BA.5 Predominant Periods 1,2, 1 3 1 1, 4 5,6 Allison Avrich Ciesla, Ryan E. Wiegand, Zachary R. Smith, Amadea Britton, Katherine E. Fleming-Dutra, Joseph Miller, Emma K. Accorsi, 5,7 5 5 1,a 1,7,a, Jennifer R. Verani, Nong Shang, Gordana Derado, Tamara Pilishvili, and Ruth Link-Gelles 1 2 3 National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA, Eagle Health Analytics, San Antonio, Texas, USA, Division of Research and Methodology, National Center for Health Statistics, Centers for Disease Control and Prevention, Hyattsville, Maryland, USA, Center for Preparedness and Response, Centers for Disease Control and Prevention, Atlanta, Georgia, USA, Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, 6 7 Atlanta, Georgia, USA, Epidemic Intelligence Service, Centers for Disease Control and Prevention, Atlanta, Georgia, USA, and US Public Health Service Commissioned Corps, Rockville, Maryland, USA Background. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) BA.2/BA.2.12.1 and BA.4/BA.5 subvariants have mutations associated with increased capacity to evade immunity when compared with prior variants. We evaluated mRNA monovalent booster dose effectiveness among persons ≥5 years old during BA.2/BA.2.12.1 and BA.4/BA.5 predominance. Methods. A test-negative, case-control analysis included data from 12 148 pharmacy SARS-CoV-2 testing sites nationwide for persons aged ≥5 years with ≥1 coronavirus disease-2019 (COVID-19)-like symptoms and a SARS-CoV-2 nucleic acid amplification test from April 2 to August 31, 2022. Relative vaccine effectiveness (rVE) was estimated comparing 3 doses of COVID-19 mRNA monovalent vaccine to 2 doses; for tests among persons ≥50 years, rVE estimates also compared 4 doses to 3 doses (≥4 months since third dose). Results. A total of 760 986 test-positive cases and 817 876 test-negative controls were included. Among individuals ≥12 years, rVE of 3 versus 2 doses ranged by age group from 45% to 74% at 1-month post vaccination and waned to 0% by 5–7 months post vaccination during the BA.4/BA.5 period. Adults aged ≥50 years (fourth dose eligible) who received 4 doses were less likely to have symptomatic SARS-CoV-2 infection compared with those with 3 doses; this rVE remained >0% through at least 3 months since last dose. For those aged ≥65 years, rVE of 4 versus 3 doses 1-month post vaccination was higher during BA.2/BA.2.12.1 (rVE = 49%; 95% confidence interval [CI], 43%– 53%) than BA.4/BA.5 (rVE = 40%; 95% CI, 36%–44%). In 50- to 64-year-olds, rVE estimates were similar. Conclusions. Monovalent mRNA booster doses provided additional protection against symptomatic SARS-CoV-2 infection during BA.2/BA.2.12.1 and BA.4/BA.5 subvariant circulation, but protection waned over time. Keywords. COVID-19; infection; monovalent boosters; SARS-CoV-2. In the United States, a monovalent coronavirus disease-2019 adults ≥65 years old (September 23, 2021), adults 18–64 (COVID-19) mRNA vaccine booster (third dose) was recom- (November 21, 2021), young adults 16–17 (December 9, mended by the Advisory Committee on Immunization 2021), and adolescents 12–15 (January 5, 2022) [1]. To address Practices at least 5 months after the last primary dose for older waning from this first booster dose, on March 29, 2022 the US Food and Drug Administration (FDA) authorized a second booster (fourth dose) of monovalent vaccine to be given at least Received 03 March 2023; editorial decision 03 April 2023; accepted 11 April 2023; published online 13 April 2023 4 months after receipt of a third dose for immunocompetent T.P. and R. L.-G. contributed equally to this work. adults aged ≥50 years, who are at increased risk of severe Correspondence: Allison Avrich Ciesla, PhD, Centers for Disease Control and Prevention, 1600 Clifton Road NE, MS H24-5, Atlanta, GA 30329 (ton4@cdc.gov); Ruth Link-Gelles, PhD, COVID-19. On May 19, 2022, a first booster (third dose) of a Centers for Disease Control and Prevention, 1600 Clifton Road NE, MS H24-5, Atlanta, GA monovalent vaccine was recommended for children aged 5–11 30329 (hzt7@cdc.gov). Open Forum Infectious Diseases years. Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023. Observational studies have demonstrated effectiveness of This work is written by (a) US Government employee(s) and is in the public domain in the US. https://doi.org/10.1093/ofid/ofad187 monovalent COVID-19 vaccine booster doses against the severe mRNA Boosters During BA.2 and BA.4/BA.5 • OFID • 1 acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta During BA.2/BA.2.12.1 predominance, all 4 pharmacy variant and Omicron BA.1 subvariant for a variety of outcomes chains with data were included in the analysis. During BA.4/ and populations [2–11]. However, Omicron BA.2/BA.2.12.1 BA.5 predominance, 1 pharmacy chain no longer contributed subvariants accounted for ≥75% of sequenced isolates in the data, whereas 2 pharmacy chains (1 new and 1 old comprising United States by April 11, 2022. The BA.2/BA.2.12.1 and of only 0.2% of the total tests during this period) began using a BA.4/BA.5 subvariants have additional mutations associated test registration form that gathered vaccination history differ- with increased capacity to evade neutralizing antibodies gener- ently, leaving this analysis with 2 chains with complete data ated in response to monovalent booster doses or BA.1 infection, during this period. Self-reported information was collected suggesting monovalent vaccines may be less effective in pre- from individuals registering for testing online, including vacci- venting infection against these subvariants [12–15]. nation history, gender, race, ethnicity, age, state of residence, To address waning monovalent vaccine effectiveness (VE) in symptom status, prior SARS-CoV-2 infections, and underlying the setting of Omicron variants, on September 1, 2022, the FDA conditions. Severe acute respiratory syndrome coronavirus 2 authorized bivalent COVID-19 mRNA vaccines for any per- NAAT date of collection, assay type, and results were reported sons who have completed a primary series, regardless of num- directly from testing sites. For detailed information on how vac- ber of doses, at least 2 months prior. Monitoring of monovalent cination history was collected, see Supplementary Information COVID-19 VE against SARS-CoV-2 infection during periods (Vaccination History Ascertainment). of BA.2/BA.2.12.1 and BA.4/BA.5 subvariant predominance is crucial to inform vaccine policy by setting a baseline to un- Study Design derstand how well newly authorized bivalent vaccines may A test-negative design was used to evaluate relative and abso- work. We analyzed data from a national, pharmacy-based lute effectiveness against symptomatic SARS-CoV-2 infection SARS-CoV-2 testing program, Increasing Community Access of 1 booster (3 doses) compared to 2 doses or unvaccinated, to Testing (ICATT) [16], to estimate age group-specific effec- and effectiveness of 2 booster doses (4 doses) compared to 3 tiveness of 1 or 2 monovalent mRNA vaccine booster doses doses or unvaccinated. At registration, persons were asked among persons aged ≥5 years during periods of Omicron whether they had an immunocompromising condition using BA.2/BA.2.12.1 and BA.4/BA.5 subvariant predominance. the following examples: immunocompromising medications, solid organ or blood stem cell transplant, human immunodefi - ciency virus (HIV), or other immunocompromising condi- METHODS tions. The respondents were excluded if they reported an Data Source immunocompromising condition. The unit of analysis was ICATT is a Department of Health and Human Services program tests: among individuals with ≥1 COVID-19-like illness symp- that contracts with pharmacy chains and laboratories to provide toms, cases were defined by a positive NAAT result and con- no-cost, drive-through SARS-CoV-2 testing at selected sites na- trols were defined by a negative NAAT result. Individuals tionwide [7–9, 16]. The ICATT program seeks to address reporting any prior SARS-CoV-2 infection were excluded COVID-19 health disparities by selecting SARS-CoV-2 testing from analysis. sites located in (1) racially and ethnically diverse communities, small towns, and rural communities as assessed using Rural- Exposures Urban Commuting Area (RUCA) codes [17] and (2) areas The main exposures were receipt of 1 booster dose for individ- with moderate to high social vulnerability based on Centers uals aged 5 to 49 years and receipt of 1 or 2 booster doses for in- for Disease Control and Prevention (CDC)/Agency for Toxic dividuals aged 50 years and older, with last dose received ≥2 Substances and Disease Registry (ATSDR) 2018 Social weeks before test dates. During the analysis time frame, Vulnerability Index (SVI) data [18, 19]. bivalent mRNA vaccines had not yet been authorized; thus, ICATT data were analyzed from SARS-CoV-2 nucleic acid reported mRNA vaccine doses were assumed to be monovalent. amplification tests (NAATs) performed during BA.2/ Individuals were excluded if they (1) were aged 5 to 49 years and BA.2.12.1 (April 2–June 11, 2022) and BA.4/BA.5 (July 2– received >3 doses or were aged ≥50 years and received >4 doses, August 31, 2022) Omicron subvariant predominance, based (2) received a booster dose earlier (<5 months) than the recom- on when each subvariant accounted for ≥75% of all sequenced mended interval, (3) received any doses of a non-mRNA vaccine, isolates in the United States [20]. Because neither set of subvar- (4) received only 1 dose of vaccine, or (5) were missing vaccina- iants accounted for at least 75% of sequenced isolates between tion information or covariables of interest. June 12 and July 1, 2022, tests performed during this period For estimating relative VE (rVE) comparing 3 versus 2 doses, were excluded from analyses. Analytic start dates for age groups the reference group consisted of individuals who had received 2 varied based on vaccine product and timing of product autho- doses and were eligible for a third dose (ie, ≥5 months since rization (Supplementary Table 1). second dose). Similarly, for estimating rVE comparing 4 versus 2 • OFID • Ciesla et al 3 doses, the reference group consisted of individuals who had last dose was calculated as the interval between month of test- received 3 doses and were eligible for a fourth dose (ie, ≥4 ing and month of the last dose. Because the interval of 2 weeks months since third dose). For absolute VE (aVE) analyses, was required between the last dose and testing date, and only the reference group for all exposure categories were unvacci- month of vaccination was available for 2 pharmacy chains, nated individuals who had not received any doses of we designated intervals as follows: 0 month (ie, testing and vac- COVID-19 vaccine. Absolute VE estimates are presented for cination in the same month), 14 to 30 days; 1 month, 14 to 60 time frames at which the next dose was recommended (ie, 5 days; 2 months, 30 to 90 days; 3 months, 60 to 120 days, and so or 4 months after the last dose and eligible for a first or second on (assuming 30-day month intervals). For example, person A booster). was vaccinated on June 1, 2022 and tested on July 31, 2022 (month interval, 1; days, 60). Person B was vaccinated on Statistical Analysis June 14, 2022 and tested on August 15, 2022 (month interval, For rVE, we estimated associations between SARS-CoV-2 in- 2; days, 60). A simulation study found VE results utilizing fection and prior mRNA vaccination status using multivariable months since vaccination was similar to using days since vacci- logistic regression. In secondary analyses, we estimated aVE by nation [9]. Statistical analyses were performed in R (version comparing odds of vaccination with 2, 3, or 4 doses of an 4.1.2; R Foundation for Statistical Computing, Vienna, mRNA vaccine versus being unvaccinated among cases and Austria). test-negative controls using multivariable logistic regression. All VE estimates were expressed as a percentage and calculated Patient Consent Statement from odds ratios (ORs) by the formula (1 − OR) × 100. This activity was reviewed by the CDC and was conducted con- Models were adjusted for calendar day of test (modeled as a sistent with applicable federal law and CDC policy (see 45 continuous linear variable), age, gender, race, ethnicity, phar- C.F.R. part 46; 21 C.F.R. part 56; 42 U.S.C. §241(d), 5 U.S.C. macy site census tract SVI, underlying conditions (presence §552a, 44 U.S.C. §3501 et seq). It was determined to be public vs absence) (list of conditions in Supplementary Table 2), state health surveillance and was not submitted for institutional re- of residence, pharmacy chain, and 7-day average of cases per view board approval and informed consent was not needed. 100 000 by site zip code (local incidence: modeled as a contin- uous linear variable). Both calendar day of test and local inci- RESULTS dence were evaluated for presence of a nonlinear relationship A total of 1 578 862 tests for SARS-CoV-2 from 12 148 sites by plotting the quartiles of each continuous variable against across 49 states, Puerto Rico, and Washington, DC met inclu- the probability of the log odds of having a positive NAAT. sion criteria (Figure 1), including 760 986 cases (395 196 during Calendar day of test had a continuous linear relationship, Omicron BA.2/BA.2.12.1 and 365 790 Omicron BA.4/BA.5 pe- whereas local incidence had a slight logarithmic relationship riods) and 817 876 test-negative controls (496 407 Omicron with the outcome. Sensitivity analyses including the log of local BA.2/BA.2.12.1 and 321 469 Omicron BA.4/BA.5) (Table 1). incidence produced no differences in the main effect. When Sixty-three percent of tests were laboratory-based NAAT race or ethnicity were not reported, they were classified as “un- (37% with rapid NAAT). Approximately 62% of tests included known” race/ethnicity and included as a separate category in were from persons aged 16–49 years, 923 007 were female analyses (Supplementary Table 2). (58%), 873 969 were White (55%), and 324 185 were Adjusted VE estimates were stratified by age group with Hispanic/Latino (21%). Among tests included in analyses, month since last vaccine dose included as a categorical variable 41% were from persons who reported receiving 3 doses (range, based on analytic start and stop dates for each age group 3% of 5-11 age group to 49% of ≥65 age group) and 34% from (Supplementary Table 1). Age group-specific models estimated persons who received 2 doses (range, 19% of ≥65 age group to rVE for 4 versus 3 doses (50–64 years, ≥65 years) and for 3 ver- 45% of 12–15 age group) of an mRNA vaccine. The proportion sus 2 doses (12–15 years, 16–49 years, 50–64 years, ≥65 years). of the study population reporting 1 of more underlying condi- For children ages 5 to 11 years, rVE estimates for 3 versus 2 dos- tions ranged from 4% (5–11 years) to 52% (≥65 years). Age dis- es were calculated overall, rather than by month since third tributions and frequencies of underlying conditions by age dose, due to the short time frame when the booster was recom- group are reported in Supplementary Table 2. mended. Absolute VE 2 doses versus unvaccinated (all age groups), 3 doses versus unvaccinated (age groups ≥12 years), and 4 doses versus unvaccinated (50–64 years, ≥65 years) Relative Vaccine Effectiveness were also estimated. For children aged 5–11 years, rVE of 3 versus 2 doses of mRNA Two of the 4 pharmacy chains collected month and year of vaccine against infection was 77% (95% confidence interval vaccination (without day) during the study period. Two phar- [CI], 54%–88%; maximum time since last dose, <1 month) macy chains collected exact day of vaccination. Months since during BA.2/BA.2.12.1 predominance and 56% (95% CI, mRNA Boosters During BA.2 and BA.4/BA.5 • OFID • 3 Figure 1. Inclusion criteria for analysis of association of booster doses of an mRNA COVID-19 vaccine with symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children, adolescents, and adults during BA.2/BA.2.12.1 (April 2, 2022–June 11, 2022) and BA.4/BA.5 (July 2, 2022–August 31, 2022) predominant periods. EUA, Emergency Use Authorization; ICATT, Increasing Community Access to Testing; NAAT, nucleic acid amplification test; y, years. 50%–60%; maximum time, 3.5 months) during BA.4/BA.5 pre- during BA.4/BA.5 (95% CI, 5%–19%) (Figure 2; dominance (Supplementary Table 3). Supplementary Table 3). Estimates of rVE for 3 versus 2 doses of mRNA vaccine for Relative VE of 3 versus 2 doses among adults ≥65 years at 1 children aged 12–15 years at 1 month post third dose was month after receipt of third dose was 45% (95% CI, 35%– 74% (95% CI, 65%–81%) during BA.2/BA.2.12.1 and 62% 54%) during BA.2/BA.2.12.1 and 50% (95% CI, 37%–61%) dur- (95% CI, 51%–70%) during BA.4/BA.5. At 5 months ing BA.4/BA.5. By 5 months post third dose receipt, rVE de- post third dose receipt, VE was 38% (95% CI, 26%–47%) during clined to 11% (95% CI, 6%–15%) during BA.2/BA.2.12.1 and BA.2/BA.2.12.1 and 11% (95% CI, −8% to 26%) during BA.4/ 13% (95% CI, 0%–24%) during BA.4/BA.5 (Figure 2; BA.5 (Figure 2; Supplementary Table 3). Supplementary Table 3). Adults aged 16–49 years at 1 month post third dose receipt At 1 month after receipt of a fourth dose, rVE for 4 versus 3 dos- had a rVE for 3 versus 2 doses of 58% (95% CI, 55%–61%) dur- es among adults aged 50–64 years was 48% (95% CI, 44%–51%) ing BA.2/BA.2.12.1 and 56% (95% CI, 52%–60%) during BA.4/ during BA.2/BA.2.12.1 and 45% (95% CI, 41%–48%) during BA.5. Relative VE was lower by 5 months after third dose re- BA.4/BA.5. In the third month since receipt of the fourth dose, ceipt for BA.2/BA.2.12.1 predominance (VE, 14%; 95% CI, rVE was 74% (95% CI, 54%–85%) during BA.2/BA.2.12.1 and 13%–16%) and BA.4/BA.5 predominance (VE, 13%; 95% CI, 38% (95% CI, 33%–41%) during BA.4/BA.5. Among adults ages 9%–17%) (Figure 2; Supplementary Table 3). ≥65 years at 1 month after receipt of a fourth dose, rVE for 4 ver- rVE for 3 versus 2 doses among those aged 50–64 years at 1 sus 3 doses was 49% (95% CI, 46%–51%) during BA.2/BA.2.12.1 month after third dose receipt was 60% (95% CI, 54%–65%) and 40% (95% CI, 36%–44%) during BA.4/BA.5. In the third during BA.2/BA.2.12.1 and 57% (95% CI, 50%–64%) during month since receipt of the fourth dose, rVE was 58% (95% CI, BA.4/BA.5. At 5 months post third dose receipt, rVE decreased 47%–66%) during BA.2/BA.2.12.1 and 33% (95% CI, 30%–36%) to 11% during BA.2/BA.2.12.1 (95% CI, 8%–13%) and 12% during BA.4/BA.5 (Figure 3; Supplementary Table 3). 4 • OFID • Ciesla et al mRNA Boosters During BA.2 and BA.4/BA.5 • OFID • 5 a b Table 1. Distribution of Characteristics for Symptomatic SARS-CoV-2 Cases and Symptomatic Test-Negative Controls Without Self-Reported Prior SARS-CoV-2 Infection During BA.2/BA.2.12.1 and BA.4/BA.5 Predominant Periods by Age Group Cases (SARS-CoV-2 Positive) Controls (SARS-CoV-2 Negative) No. (%) No. (%) Doses of mRNA COVID-19 Vaccine No. (%) … … … Characteristic BA.2/BA.2.12.1 BA.4/BA.5 BA.2/BA.2.12.1 BA.4/BA.5 Unvaccinated 2 3 4 Overall 5–11 Years Old Vaccination History … … … … … … … … … Unvaccinated 8335 (53) 8298 (64) 20 307 (52) 11 682 (57) 48 622 (100) 0 (0) 0 (0) 0 (NA) 48 622 (55) 2 Doses 7403 (47) 4209 (32) 18 811 (48) 7119 (34) 0 (0) 37 542 (100) 0 (0) 0 (NA) 37 542 (42) 3 Doses 12 (0.08) 505 (4) 90 (0.2) 1859 (9) 0 (0) 0 (0) 2466 (100) 0 (NA) 2466 (3) 4 Doses 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (NA) 0 (0) SARS-CoV-2 Positive … … … … … … … … … BA.2/BA2.12.1 15 750 (100) 0 (0) 0 (0) 0 (0) 8335 (17) 7403 (20) 12 (0.5) 0 (NA) 15 750 (18) BA.4/BA.5 0 (0) 13 012 (100) 0 (0) 0 (0) 8298 (17) 4209 (11) 505 (20) 0 (NA) 13 012 (15) SARS-CoV-2 Negative … … … … … … … … … BA.2/BA.2.12.1 0 (0) 0 (0) 39 208 (100) 0 (0) 20 307 (42) 18 811 (50) 90 (4) 0 (NA) 39 208 (44) BA.4/BA.5 0 (0) 0 (0) 0 (0) 20 660 (100) 11 682 (24) 7119 (19) 1859 (75) 0 (NA) 20 660 (23) SARS-CoV-2 Test Type, NAAT Only … … … … … … … … … Rapid 5849 (37) 5150 (40) 17 761 (45) 9604 (46) 22 165 (46) 15 315 (41) 884 (36) 0 (NA) 38 364 (43) Laboratory-based 9901 (63) 7862 (60) 21 447 (55) 11 056 (54) 26 457 (54) 22 227 (59) 1582 (64) 0 (NA) 50 266 (57) Underlying chronic conditions , any (%) 524 (3) 492 (4) 1320 (3) 804 (4) 1630 (3) 1397 (4) 113 (5) 0 (NA) 3140 (4) 12–15 Years Old Vaccination History … … … … … … … … … Unvaccinated 3545 (33) 3566 (40) 6383 (34) 4114 (33) 17 608 (100) 0 (0) 0 (0) 0 (NA) 17 608 (34) 2 Doses 5343 (49) 3762 (42) 8433 (44) 5409 (44) 0 (0) 22 947 (100) 0 (0) 0 (NA) 22 947 (45) 3 Doses 1926 (18) 1581 (18) 4187 (22) 2853 (23) 0 (0) 0 (0) 10 547 (100) 0 (NA) 10 547 (21) 4 Doses 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (NA) 0 (0) SARS-CoV-2 Positive … … … … … … … … … BA.2/BA2.12.1 10 814 (100) 0 (0) 0 (0) 0 (0) 3545 (20) 5343 (23) 1926 (18) 0 (NA) 10 814 (21) BA.4/BA.5 0 (0) 8909 (100) 0 (0) 0 (0) 3566 (20) 3762 (16) 1581 (15) 0 (NA) 8909 (17) SARS-CoV-2 Negative … … … … … … … … … BA.2/BA.2.12.1 0 (0) 0 (0) 19 003 (100) 0 (0) 6383 (36) 8433 (37) 4187 (40) 0 (NA) 19 003 (37) BA.4/BA.5 0 (0) 0 (0) 0 (0) 12 376 (100) 4114 (23) 5409 (24) 2853 (27) 0 (NA) 12 376 (24) SARS-CoV-2 Test Type, NAAT Only … … … … … … … … … Rapid 4095 (38) 3395 (38) 8644 (45) 5948 (48) 7904 (45) 10 487 (46) 3691 (35) 0 (NA) 22 082 (43) Laboratory-based 6719 (62) 5514 (62) 10 359 (55) 6428 (52) 9704 (55) 12 460 (54) 6856 (65) 0 (NA) 29 020 (57) Underlying chronic conditions , any (%) 504 (5) 492 (6) 1068 (6) 760 (6) 904 (5) 1271 (6) 649 (6) 0 (NA) 2824 (6) 16–49 Years Old Vaccination History … … … … … … … … … Unvaccinated 47 383 (19) 55 070 (24) 67 460 (22) 47 171 (24) 217 084 (100) 0 (0) 0 (0) 0 (NA) 217 084 (22) 2 Doses 91 712 (37) 89 960 (39) 98 626 (33) 74 942 (38) 0 (0) 355 240 (100) 0 (0) 0 (NA) 355 240 (36) 6 • OFID • Ciesla et al Table 1. Continued Cases (SARS-CoV-2 Positive) Controls (SARS-CoV-2 Negative) No. (%) No. (%) Doses of mRNA COVID-19 Vaccine No. (%) … … … Characteristic BA.2/BA.2.12.1 BA.4/BA.5 BA.2/BA.2.12.1 BA.4/BA.5 Unvaccinated 2 3 4 Overall 3 Doses 106 149 (43) 84 893 (37) 135 206 (45) 76 508 (39) 0 (0) 0 (0) 402 756 (100) 0 (NA) 402 756 (41) 4 Doses 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (NA) 0 (0) SARS-CoV-2 Positive … … … … … … … … … BA.2/BA2.12.1 245 244 (100) 0 (0) 0 (0) 0 (0) 47 383 (22) 91 712 (26) 106 149 (26) 0 (NA) 245 244 (25) BA.4/BA.5 0 (0) 229 923 (100) 0 (0) 0 (0) 55 070 (25) 89 960 (25) 84 893 (21) 0 (NA) 229 923 (24) SARS-CoV-2 Negative … … … … … … … … … BA.2/BA.2.12.1 0 (0) 0 (0) 301 292 (100) 0 (0) 67 460 (31) 98 626 (28) 135 206 (34) 0 (NA) 301 292 (31) BA.4/BA.5 0 (0) 0 (0) 0 (0) 198 621 (100) 47 171 (22) 74 942 (21) 76 508 (19) 0 (NA) 198 621 (20) SARS-CoV-2 Test Type, NAAT Only … … … … … … … … … Rapid 89 303 (36) 83 912 (36) 114 487 (38) 80 574 (41) 90 379 (42) 149 267 (42) 128 630 (32) 0 (NA) 368 276 (38) Laboratory-based 155 941 (64) 146 011 (64) 186 805 (62) 118 047 (59) 126 705 (58) 205 973 (58) 274 126 (68) 0 (NA) 606 804 (62) Underlying chronic conditions , any (%) 41 453 (17) 39 310 (17) 56 114 (19) 36 666 (18) 34 756 (16) 61 899 (17) 76 888 (19) 0 (NA) 173 543 (18) 50–64 Years Old Vaccination History … … … … … … … … … Unvaccinated 10 376 (13) 9526 (13) 11 193 (14) 6906 (13) 38 001 (100) 0 (0) 0 (0) 0 (0) 38 001 (13) 2 Doses 25 633 (33) 25 415 (34) 22 712 (28) 17 681 (33) 0 (0) 91 441 (100) 0 (0) 0 (0) 91 441 (32) 3 Doses 40 378 (51) 32 282 (44) 42 960 (53) 21 795 (40) 0 (0) 0 (0) 137 415 (100) 0 (0) 137 415 (48) 4 Doses 2466 (3) 6712 (9) 3876 (5) 7851 (14) 0 (0) 0 (0) 0 (0) 20 905 (100) 20 905 (7) SARS-CoV-2 Positive … … … … … … … … … BA.2/BA2.12.1 78 853 (100) 0 (0) 0 (0) 0 (0) 10 376 (27) 25 633 (28) 40 378 (29) 2466 (12) 78 853 (27) BA.4/BA.5 0 (0) 73 935 (100) 0 (0) 0 (0) 9526 (25) 25 415 (28) 32 282 (23) 6712 (32) 73 935 (26) SARS-CoV-2 Negative … … … … … … … … … BA.2/BA.2.12.1 0 (0) 0 (0) 80 741 (100) 0 (0) 11 193 (29) 22 712 (25) 42 960 (31) 3876 (19) 80 741 (28) BA.4/BA.5 0 (0) 0 (0) 0 (0) 54 233 (100) 6906 (18) 17 681 (19) 21 795 (16) 7851 (38) 54 233 (19) SARS-CoV-2 Test Type, NAAT Only … … … … … … … … … Rapid 30 363 (39) 26 123 (35) 31 372 (39) 20 950 (39) 15 489 (41) 38 267 (42) 48 871 (36) 6181 (30) 108 808 (38) Laboratory-based 48 490 (61) 47 812 (65) 49 369 (61) 33 283 (61) 22 512 (59) 53 174 (58) 88 544 (64) 14 724 (70) 178 954 (62) Underlying chronic conditions , any (%) 28 686 (36) 28 448 (38) 31 303 (39) 21 748 (40) 13 402 (35) 35 344 (39) 52 916 (39) 8523 (41) 110 185 (38) ≥65 Years Old Vaccination History … … … … … … … … … Unvaccinated 3661 (8) 2948 (7) 4560 (8) 2508 (7) 13 677 (100) 0 (0) 0 (0) 0 (0) 13 677 (8) 2 Doses 8723 (20) 8805 (22) 8971 (16) 6704 (19) 0 (0) 33 203 (100) 0 (0) 0 (0) 33 203 (19) 3 Doses 26 181 (59) 16 527 (41) 31 790 (57) 12 247 (34) 0 (0) 0 (0) 86 745 (100) 0 (0) 86 745 (49) 4 Doses 5970 (13) 11 731 (29) 10 842 (19) 14 120 (40) 0 (0) 0 (0) 0 (0) 42 663 (100) 42 663 (24) SARS-CoV-2 Positive … … … … … … … … … BA.2/BA2.12.1 44 535 (100) 0 (0) 0 (0) 0 (0) 3661 (27) 8723 (26) 26 181 (30) 5970 (14) 44 535 (25) BA.4/BA.5 0 (0) 40 011 (100) 0 (0) 0 (0) 2948 (22) 8805 (27) 16 527 (19) 11 731 (27) 40 011 (23) Absolute Vaccine Effectiveness Estimates of aVE for 2, 3, and 4 doses compared to no doses (unvaccinated) during BA.2/BA.2.12.1 and BA.4/BA.5 pre- dominance were similar across all age groups and declined by time since last dose receipt (Supplementary Figures 1–3). In aVE models, 2 doses were no longer effective by 6 months after receipt of the second dose for all age groups and during both subvariant periods except for children aged 5–11 years where 2 doses remained effective throughout the BA.2/BA.2.12.1 study period. Three doses were no longer effective by 6 months after receipt of the third dose for those ≥16 years. DISCUSSION In this analysis of national pharmacy testing data, monovalent mRNA boosters provided additional protection against symp- tomatic SARS-CoV-2 infection among adults, adolescents, and children across BA.2/BA.2.12.1 and BA.4/BA.5 predominant periods. During BA.4/BA.5, protection among adults ≥50 years declined moderately and remained above zero 4 months after receipt of the second booster dose. Among adolescents 12–15 years old, the first booster (dose 3) was no longer effective by 5 months after receipt, and by 6 months after receipt among those 16–49 years old. In March 2022, the FDA authorized a fourth monovalent vaccine dose for all adults aged 50 years and older 4 months af- ter receiving their third dose. As of September 21, 2022, a mi- nority of adults ≥50 years (35.5%) and ≥65 years (42.8%) had received a second booster (fourth dose) [21]. However, the cur- rent study demonstrates added benefit of the fourth dose against infection, particularly 3–5 months after vaccination. These results are consistent with immunogenicity studies dem- onstrating an increase in antibodies from a fourth dose after al- most a 10-fold antibody decrease due to waning after the third dose, and studies evaluating effectiveness of 4 versus 3 doses of mRNA vaccine [22–26]. Relative VE of a third mRNA dose over a second waned with time after receipt of the third dose. Similar waning was seen during both Omicron periods in this analysis. During pre-Omicron, waning of rVE for 3 versus 2 doses has been ob- served among adults against infection but not against more se- vere outcomes [27]. Previous analyses from this ICATT platform have noted waning of aVE against infection among adolescents aged 12–15 years [9] and adults [8] during the early Omicron period; our results suggest continued waning oc- curred during this study period after receipt of 3 doses of an mRNA vaccine. A similar magnitude of waning was observed across all age groups. To contextualize interpretation of our primary analysis of rVE, we evaluated aVE for 4, 3, and 2 doses versus no doses, and we found similar patterns of waning after receipt of 2 or 3 doses. Absolute VE estimates for 2 and 3 doses at 5 months mRNA Boosters During BA.2 and BA.4/BA.5 • OFID • 7 Table 1. Continued Cases (SARS-CoV-2 Positive) Controls (SARS-CoV-2 Negative) No. (%) No. (%) Doses of mRNA COVID-19 Vaccine No. (%) … … … Characteristic BA.2/BA.2.12.1 BA.4/BA.5 BA.2/BA.2.12.1 BA.4/BA.5 Unvaccinated 2 3 4 Overall SARS-CoV-2 Negative … … … … … … … … … BA.2/BA.2.12.1 0 (0) 0 (0) 56 163 (100) 0 (0) 4560 (33) 8971 (27) 31 790 (37) 10 842 (25) 56 163 (32) BA.4/BA.5 0 (0) 0 (0) 0 (0) 35 579 (100) 2508 (18) 6704 (20) 12 247 (14) 14 120 (33) 35 579 (20) SARS-CoV-2 Test Type, NAAT Only … … … … … … … … … Rapid 18 896 (42) 14 612 (37) 22 846 (41) 13 433 (38) 6067 (44) 14 602 (44) 34 655 (40) 14 463 (34) 69 787 (40) Laboratory-based 25 639 (58) 25 399 (63) 33 317 (59) 22 146 (62) 7610 (56) 18 601 (56) 52 090 (60) 28 200 (66) 106 501 (60) Underlying chronic conditions , any (%) 22 528 (51) 21 051 (53) 28 937 (52) 19 349 (54) 5776 (42) 17 311 (52) 45 804 (53) 22 974 (54) 91 865 (52) Abbreviations: COVID-19, coronavirus disease 2019; NA, not applicable; NAAT, nucleic acid amplification test; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. BA.2/BA.2.12.1: April 2, 2022–June 11, 2022. BA.4/BA.5: July 2, 2022–August 31, 2022. Only month and year of receipt were reported for each vaccination dose from some participating pharmacies; therefore, the number of months between a vaccine dose and testing is a whole number calculated as the difference between the month and year of testing and the month and year of the vaccine dose. Persons reporting a non-mRNA vaccination were excluded from analyses. For doses received in the same month or the month before SARS-CoV-2 testing, an additional question was asked to specify whether the dose was received ≥2 weeks before testing, and only doses received ≥2 weeks before testing were included. Rapid NAAT was performed onsite on self-collected nasal swabs using ID Now (Abbott Diagnostics Scarborough Inc.) and Accula (Thermo Fisher Scientific). Laboratory-based NAAT was performed on self-collected nasal swabs at contracted laboratories using a variety of testing platforms. Underlying conditions included on the survey were as follows: heart conditions, high blood pressure, overweight or obesity, diabetes, current or former smoker, kidney failure or end-stage renal disease, cirrhosis of the liver, chronic lung disease (such as chronic obstructive pulmonary disease, moderate to severe asthma, cystic fibrosis, or pulmonary embolism). Figure 2. Adjusted mRNA COVID-19 relative vaccine effectiveness of 3 doses compared to 2 doses against symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during BA.2/BA.2.12.1 (April 2, 2022–June 11, 2022) and BA.4/BA.5 (July 2, 2022–August 31, 2022) periods by time since third dose receipt. Multivariable logistic regression models controlling for calendar day of test (continuous), age, gender, race, ethnicity, 2018 Centers for Disease Control and Prevention census tract social vulnerability index, underlying conditions (presence vs absence—included on the survey were heart conditions, high blood pressure, overweight or obesity, di- abetes, current or former smoker, kidney failure or end-stage renal disease, cirrhosis of the liver, chronic lung disease [such as chronic obstructive pulmonary disease, mod- erate to severe asthma, cystic fibrosis, or pulmonary embolism]), individual state of residence, pharmacy chain, and average cases per 100 000 by site zip code (over the last 7 days) were used to estimate vaccine effectiveness. Tests included in the reference group were from persons receiving 2 doses and eligible for a third dose (ie, if 5 months had passed since second dose). (A) Children aged 12–15 years. (B) Young adults aged 16–49 years. (C) Adults aged 50–64 years. (D) Adults aged 65 years and older. post receipt were zero (ie, no protection), indicating rVE likely in antibody levels and neutralizing activity [26] underscore the approximates aVE. Significantly negative rVE estimates ob- continued need for people of all ages to remain current with served among adults aged ≥50 years during BA.4/BA.5 pre- their COVID-19 vaccinations. Despite the emergence of new dominance 7–9 months post receipt of a third dose compared subvariants, mRNA vaccines continue to demonstrate at least to those with 2 doses and higher aVE by time since fourth short-term effectiveness against infection and longer term pro- dose may represent residual confounding, potentially due to tection against more severe outcomes. Recently approved underreported prior SARS-CoV-2 infection. COVID-19 bivalent mRNA vaccines, more closely matching A recent study by Petrie et al [25] reported similar findings currently circulating variants, appear to provide increased pro- with modest to high protection after the third dose (or first tection [32–34]. booster) compared to a primary series that waned to null by 6 months after receipt of the third dose. Petrie et al [25] found Limitations no significant VE after the second booster dose when compared There are several important limitations of this study. First, to a single booster dose, whereas an earlier study from Israel these data are from pharmacies selected based on RUCA codes confirmed similar VE to our study with a relative VE of 52% [17] and SVI [19] to better reach underserved communities; (95% CI, 49%–54%) in the first month after the fourth dose therefore, the population included may not be representative [28]. Other recent findings showing that 4 doses are effective of the general US population, or even geographic areas where against severe COVID-19 disease [29–31], and have an increase reporting pharmacy sites are located. Second, the population 8 • OFID • Ciesla et al Figure 3. Adjusted mRNA COVID-19 relative vaccine effectiveness of 4 doses compared to 3 doses against symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during BA.2/BA.2.12.1 (April 2, 2022–June 11, 2022) and BA.4/BA.5 (July 2, 2022–August 31, 2022) periods by time since fourth dose receipt. Multivariable logistic regression models controlling for calendar day of test (continuous), age, gender, race, ethnicity, 2018 Centers for Disease Control and Prevention census tract social vulnerability index, underlying conditions (presence vs absence—included on the survey were heart conditions, high blood pressure, overweight or obesity, di- abetes, current or former smoker, kidney failure or end-stage renal disease, cirrhosis of the liver, chronic lung disease [such as chronic obstructive pulmonary disease, mod- erate to severe asthma, cystic fibrosis, or pulmonary embolism]), individual state of residence, pharmacy chain, and average cases per 100 000 by site zip code (over the last 7 days) were used to estimate vaccine effectiveness. Tests included in the reference group were from persons receiving 3 doses and eligible for a fourth dose (ie, if 5 months had passed since third dose). (A) Adults aged 50–64 years. (B) Adults aged 65 years or older. included is based on persons accessing pharmacies for Our study highlights how VE against SARS-CoV-2 infection SARS-CoV-2 testing. Changes in individual testing practices changes over time, which can signal reduced effectiveness and increased use of home tests [35], by presence of symptoms against new variants, waning vaccine protection, or both. We or vaccination status, could introduce selection bias. Third, we found booster doses provide added protection against did not have information on community or household-level ex- SARS-CoV-2 infection among immunocompetent persons posures, individual prevention behaviors (eg, mask use), or ages 5 years and older during BA.2/BA.2.12.1 and BA.4/BA.5 other confounders [36]. Those who remain unvaccinated may predominance. However, protection waned in the months after be fundamentally different from vaccinated individuals. vaccination; although little to no waning was observed after the Fourth, vaccination status and prior infection were self- fourth dose in older adults, long-term follow up was not avail- reported and subject to recall bias; therefore, there is a potential able. Recently introduced bivalent COVID-19 mRNA vaccine for misclassification. As of June 2022, 58.7% of the US popula- doses have the potential to restore protection against circulating tion had infection-induced seroprevalence; however, only 21% new Omicron subvariants. Our study supports the need to stay (during BA.2/BA.2.12.1) and 31% (during BA.4/BA.5) of the up to date on recommended doses of COVID-19 vaccines. initial sample reported prior infection [37], indicating underre- Supplementary Data porting of prior infection. Given the poor characterization of Supplementary materials are available at Open Forum Infectious Diseases prior infection in this sample, the present study included online. Consisting of data provided by the authors to benefit the reader, the only individuals who indicated no prior infection. posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the correspond- ing author. CONCLUSIONS Acknowledgments Although the goal of the US COVID-19 vaccination program is We thank Stephanie J. Schrag (Centers for Disease Control and prevention of severe disease [38], VE against symptomatic in- Prevention [CDC]). fection can provide important insight to help understand Author contributions. AAC and REW had full access to the data used in the how vaccines are working in the real world, especially in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. AAC, RL-G, AB, KEF-D, JRV, TP, and REW contrib- context of emerging variants and before estimates against uted to concept and design. All authors contributed to acquisition, analysis, more severe outcomes are available. Continued monitoring of or interpretation of data. AAC, RL-G, TP, and REW drafted the manu- COVID-19 VE is crucial to inform and guide future vaccine script. All authors contributed to critical revision of the manuscript for im- policy decisions. portant intellectual content. AAC, NS, GD, and REW contributed to mRNA Boosters During BA.2 and BA.4/BA.5 • OFID • 9 18. Flanagan BE, Gregory EW, Hallisey EJ, Heitgerd JL, Lewis B. A social vulnerability statistical analysis. JM obtained funding. ZRS, AB, KEF-D, JM, JRV, TP, index for disaster management. J Homel Secur Emerg Manag 2011; 8:1–22. and RL-G contributed to administrative, technical, or material support. 19. U.S. Centers for Disease Control and Prevention. CDC/ATSDR Social JM, TP, RL-G, and REW supervised the work. Vulnerability Index (2018). Available at: https://www.atsdr.cdc.gov/placeandhe Disclaimer. The findings and conclusions in this report are those of the alth/svi/index.html. Accessed 19 October 2022. authors and do not necessarily represent the official position of the CDC. 20. Centers for Disease Control and Prevention. SARS-CoV-2 Variant Proportions. Financial support. Funding for the Increasing Community Access to Available at: https://data.cdc.gov/Laboratory-Surveillance/SARS-CoV-2-Varia Testing platform is provided by the US Department of Health and nt-Proportions/jr58-6ysp. Accessed 28 July 2022. Human Services. Funding for this analysis was provided by the CDC. 21. Centers for Disease Control and Prevention. COVID-19 Vaccinations in the Potential conflicts of interest. None reported. United States. Available at: https://covid.cdc.gov/covid-data-tracker/#vaccina tions_vacc-people-additional-dose-totalpop. Accessed 27 September 2022. Role of the funder/sponsor. 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Journal

Open Forum Infectious Diseases – Oxford University Press

Published: Apr 13, 2023

Keywords: COVID-19; infection; monovalent boosters; SARS-CoV-2

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