Effectiveness of a fourth dose of mRNA-1273 against COVID-19 among older adults in the United States: Interim results from an observational cohort study

We evaluated relative vaccine effectiveness (rVE) of 4- vs. 3-dose mRNA-1273 against SARS-CoV-2 infection, and COVID-19 hospitalization and death in immunocompetent adults aged ≥50 years at Kaiser Permanente Southern California. We included 178,492 individuals who received a fourth dose of mRNA-1273, and 178,492 randomly selected 3-dose recipients who were matched to 4-dose recipients by age, sex, race/ethnicity, and third dose date. Adjusted 4- vs. 3-dose rVE against SARS-CoV-2 infection, COVID-19 hospitalization, and COVID-19 hospitalization death were 25.9 % (23.5 %, 28.2 %), 67.3 % (58.7 %, 74.1 %), and 72.5 % (-35.9 %, 95.2 %), respectively. Adjusted rVE against SARS-CoV-2 infection ranged between 19.8 % and 39.1 % across subgroups. Adjusted rVE against SARS-CoV-2 infection and COVID-19 hospitalization decreased 2–4 months after the fourth dose. Four mRNA-1273 doses provided significant protection against COVID-19 outcomes compared with 3 doses, consistent in various subgroups of demographic and clinical characteristics, although rVE varied and waned over time.


Introduction
As of November 2022, coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in >101 million infections and >1 million deaths in the United States [1]. Individuals aged !50 years are at a higher risk of severe COVID-19 disease [2]. In March 2022, the Food and Drug Administration authorized a second monovalent mRNA-based booster dose, 4 months after dose 3 for individuals at high risk of severe disease, including immunocompetent adults aged !50 years [3].
Studies have reported on the significant protection of 4 doses (vs. unvaccinated) of mRNA vaccines against SARS-CoV-2 infection, and COVID-19 hospitalization and death [4]. Although some studies have evaluated the 4-vs. 3-dose relative vaccine effectiveness (rVE) of mRNA vaccines [5,6], data are lacking for mRNA-1273 specifically among the general US population aged !50 years and by subgroups. Additionally, while the uptake of the primary monovalent series in the older US population is high (>94 % for ! 65 years), booster uptake is low (monovalent second booster, <40 % for !50 years; bivalent booster, 39 % for !65 years) [7]. Consequently, better understanding of the 4-vs. 3-dose rVE of mRNA-1273 is of public health importance. We evaluated rVE of 4 doses of mRNA-1273 compared to 3 doses against SARS-CoV-2 infection and severe COVID-19 disease in immunocompetent individuals aged !50 years by demographic and clinical subgroups during the omicron period.

Methods
Study setting is described in detail in our prior publications [8]. Immunocompetent Kaiser Permanente Southern California (KPSC) members aged !50 years were included ( Supplementary Fig. 1 The study included eligible individuals who received a fourth dose of mRNA-1273 !120 days after the third dose (4-dose group), and eligible individuals who received 3 doses of mRNA-1273 (3dose group) as of the index date. Three-dose recipients were randomly selected and 1:1 matched to 4-dose recipients by age, sex, race/ethnicity, and third dose date. Index date was defined as the date of the fourth dose for the 4-dose recipients; the same index date was assigned to their matched 3-dose vaccinated counterparts. Fourth doses were accrued between 03/29/2022 and 07/31/2022, with follow-up through 08/31/2022. Those who received a COVID-19 vaccine other than mRNA-1273 prior to index date; received a second, third, or fourth dose of mRNA-1273 <24 days, <150 days, or <120 days from their previous dose, respectively; or received any COVID-19 vaccine, died, or had a COVID-19 outcome <14 days after the index date were excluded.
Exposure of interest was 3 or 4 doses of monovalent mRNA-1273. Outcomes were SARS-CoV-2 infection, COVID-19 hospitalization, and COVID-19 hospital death [8]. We identified symptomatic vs. asymptomatic SARS-CoV-2 infections using natural language processing [9]. We considered SARS-CoV-2 infection incident if there was no COVID-19 diagnosis code or SARS-CoV-2 positive test in the 90 days prior. Individuals were followed for outcomes from 14 days after the index date until end of followup (08/31/2022), termination of KPSC membership, death, or receipt of an additional COVID-19 vaccine, whichever occurred first. Individuals in the 3-dose group who received an eligible fourth dose during follow-up were censored and started contributing 4dose person-time, 14 days after their fourth dose.
We described characteristics of the 3-dose and 4-dose groups. Covariates included in the multivariable models, along with matching variables, were selected based on scientific relevance or absolute standardized differences >0.1. Incidence rates (IR) and cumulative incidence were calculated. Hazard ratios (HR) were estimated using Cox proportional hazards regression. rVE (%) was calculated as (1 -HR) Â 100 when HR was 1, and ([1/HR] -1) Â 100 when HR was >1. All statistical analyses were conducted using SAS software version 9.4, Cary, USA. This study was approved by the KPSC Institutional Review Board.

Results
Our study included 178,492 immunocompetent adults aged !50 years who received 4 doses of mRNA-1273, and 178,492 matched counterparts who received 3 doses ( Supplementary  Fig. 1). The cohort was 55 % female and 44 % non-Hispanic White, with a mean age of 69 years (standard deviation, 10) (  Fig. 2B). The median follow-up time was 1.08 months (interquartile range [IQR] 0.36-2.33 months) and 3.06 months (IQR 2.04-3.94 months) for the 3-dose and 4-dose groups, respectively. A total of 78,154 (44 %) individuals originally in the 3-dose group who received a fourth dose of mRNA-1273 during the vaccination accrual period (03/29/2022 -07/31/2022) and met the inclusion criteria for the 4-dose group began to contribute 4-dose persontime 14 days after the fourth dose.
Overall, we observed a lower 4-vs. 3-dose rVE compared to our previous studies spanning delta and omicron periods [11]. Lower rVE may be partially explained by antigen test results included in this study; some of our previous studies were limited to samples successfully sequenced by polymerase chain reaction (PCR), potentially indicative of higher viral load and more severe disease. In this study, higher rVE against PCR-confirmed infection (32.6 % [29.2 %,35.9 %]) was observed in a sensitivity analysis. This study also included older populations (!50 years) only, unlike our previous reports. Further, substantial immune escape from both vaccinationand infection-induced neutralizing antibodies has been reported for BA.2.12.1, BA.4, and BA.5, with lower neutralizing antibody titers as compared to BA.1 and BA.2 [12]. Additionally, recent data on binding and neutralizing antibodies and B-cell and T-cell immunity suggest that prior infection can decrease subsequent immunity [13]. Differential immune imprinting in individuals with immunity against earlier variants could compromise immune responses to omicron subvariants. Such immune modulations may partially explain the lower rVE observed in our study, particularly, the null rVE against SARS-CoV-2 infection 4-5 months after the fourth dose. Lastly, rVE estimates represent additional protection provided by the fourth dose compared to the third dose, and should be interpreted accordingly. Nevertheless, despite the low rVE against SARS-CoV-2 infection (26 %), the rVE against COVID-19 hospitalization remained high.
Our study has several strengths. This was a population-based, real-world study in an integrated health care system with a large, diverse, and stable population. KPSC's comprehensive EHR enabled accurate capture of exposure, outcomes, and covariates. The matched cohort design increased generalizability to the older US population, unlike test-negative designs, which limit generalizability to those who are tested. We reported rVE of 4 doses vs. 3 doses,    When the hazard ratio or its 95 % CI was >1, the rVE or its 95% CI was transformed as ([1/hazard ratio] -1) Â 100. Abbreviations: CI = confidence interval; N/A = not applicable; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2. a Adjusted for covariates age, sex, race/ethnicity, index date (in months), time between third dose and index date, history of SARS-CoV-2 infection, and medical center area. b SARS-CoV-2 infection was defined as a positive molecular/antigen test or a COVID-19 diagnosis code for both symptomatic and asymptomatic cases. c COVID-19 hospitalization was defined as hospitalization with a SARS-CoV-2 positive test or a COVID-19 diagnosis, or a hospitalization occurring 7 days after a SARS-CoV-2 positive test and confirmed by pre-determined criteria or manual chart review [8]. d Age and medical center area were removed from adjustment set due to lack of model convergence. e Symptoms were identified by computerized natural language processing algorithm developed through an iterative process to identify 12 common COVID-19-related symptoms (fever, cough, headache, fatigue, dyspnea, chills, sore throat, myalgia, anosmia, diarrhea, vomiting/nausea, and abdominal pain) in the 14 days prior to 7 days after the infection date among individuals with a positive SARS-CoV-2 molecular/antigen test or a COVID-19 diagnosis. f Medical center area was removed from adjustment set due to lack of model convergence. as opposed to using unvaccinated individuals as a comparator group, to reduce selection bias. Lastly, we confirmed hospitalizations ''for" COVID-19 (rather than ''with" a COVID-19 diagnosis) by manual chart review. Nonetheless, our study has limitations. Due to the observational study design, there may be residual confounding, such as healthcare seeking behaviors. However, since we compared 4-dose vs. 3-dose recipients instead of unvaccinated individuals, we expect such unmeasured confounding to be minimal. Non-differential misclassification of SARS-CoV-2 infection may have occurred due to false positive/negative results or erroneous diagnosis codes. Although we did not evaluate rVE associated with specific variants, this study was conducted during a period of omicron predominance, and most of our cases were likely infected by omicron sublineages. Additionally, it is difficult to make meaningful conclusions from the rVE estimated for the 4-5 month-period after the index date due to limited sample size and short follow-up. Lastly, we only included individuals aged !50 years and had a limited sample size for severe outcomes. The fourth dose was authorized in March 2022 for adults aged !50 years, and >95 % of fourth dose recipients at KPSC during the study period were !50 years of age.
Four doses of mRNA-1273 provided additional protection against SARS-CoV-2 infection and COVID-19 hospitalization compared to 3 doses in individuals aged !50 years across various subgroups of demographic/clinical characteristics, although rVE varied and waned over time.

Data availability
The data presented in this study are not publicly available due to privacy concerns.

Declaration of Competing Interest
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JHK, LSS, LQ, BKA, YL, JET, GSL, AF, FX, SQ, and HFT are employees of Kaiser Permanente Southern California, which has been contracted by Moderna to conduct this study. KJB is an adjunct investigator at Kaiser Permanente Southern California. SC was an employee of and shareholder in Moderna, Inc. at the time of the study. CAT was an employee of and a shareholder in Moderna Inc. at the time of analysis conception; CAT is currently an employee of AstraZeneca. JHK received funding from GlaxoSmithKline unrelated to this manuscript. LSS received funding from GlaxoSmithKline and Dynavax unrelated to this manuscript. LQ received funding from GlaxoSmithKline and Dynavax unrelated to this manuscript. BKA received funding from GlaxoSmithKline, Dynavax, Genentech, and Pfizer unrelated to this manuscript. YL received funding from GlaxoSmithKline and Pfizer unrelated to this manuscript. JET received funding from Pfizer unrelated to this manuscript. GSL received funding from GlaxoSmithKline unrelated to this manuscript. AF received funding from Pfizer, GlaxoSmithKline, and Gilead unrelated to this manuscript. KJB received funding from GlaxoSmithKline, Dynavax, Pfizer, and Gilead unrelated to this manuscript. FX received funding from Pfizer, Janssen, and Hologic unrelated to this manuscript. SQ received funding from Dynavax unrelated to this manuscript. HFT received funding from Glax-oSmithKline unrelated to this manuscript; HFT also served on advisory boards for Janssen and Pfizer.  The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. The corresponding author (the guarantor) is responsible for the overall content and conduct of the study, and the decision to publish.

Data availability statement
The data presented in this study are not publicly available due to privacy concerns.