Long-term safety and efficacy of COVE study open-label and booster phases

doi:10.21203/rs.3.rs-3900939/v1

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Long-term safety and efficacy of COVE study open-label and booster phases

https://doi.org/10.21203/rs.3.rs-3900939/v1

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published 29 Aug, 2024

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Vaccination with two injections of mRNA-1273 (100-μg) was shown to be safe and efficacious at preventing coronavirus disease 2019 (COVID-19) in the Coronavirus Efficacy (COVE) trial at completion of the blinded part of the study. We present the final report of the longer-term safety and efficacy data of the primary vaccination series plus a 50-μg booster dose administered in Fall 2021. The booster safety profile was consistent with that of the primary series. Incidences of COVID-19 and severe COVID-19 were higher during the Omicron BA.1 than Delta variant waves and boosting versus non-boosting was associated with significant reductions for both. In an exploratory Cox regression model adjusted for time-varying covariates, a longer interval between primary vaccination and boosting was associated with a significantly lower incidence of COVID-19 during the Omicron BA.1 wave. Boosting elicited greater immune responses against ancestral SARS-CoV-2 than the primary series, irrespective of prior SARS-CoV-2 infection.

ClinicalTrials.gov: NCT04470427

Health sciences/Diseases/Infectious diseases

Health sciences/Health care/Disease prevention

The mRNA-1273 vaccine two-injection primary series demonstrated 93.2% efficacy against coronavirus disease 2019 (COVID-19) and acceptable safety at the completion of the blinded, randomized, placebo-controlled Part A of the Coronavirus Efficacy (COVE) trial in adults with a median follow-up time of 5.3 months.^1,2 The vaccine has been approved by many regulatory authorities and has been widely administered globally to children and adults.^3–6 Real world effectiveness was also demonstrated against COVID-19, especially severe disease and death.^7–11

The mRNA-1273 vaccine exhibited robust antibody responses across age groups, neutralized severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants and was effective against SARS-CoV-2 variants circulating during the blinded and open-label periods of the COVE trial.^{1,2,5–7,10,12–16} An additional 50-µg mRNA-1273 vaccine dose was authorized as a first booster dose and has demonstrated improved immune responses and effectiveness against variants.^14,17–20 As variants became more divergent, such as the Omicron family of variants, updated versions of mRNA-1273 bivalent and monovalent-containing variant spike mRNAs^21–25 have been authorized and/or approved in multiple regions.^26,27

Following the Emergency Use Authorization (EUA) for COVID-19 vaccines in December 2020, the COVE protocol was amended to include an open-label component (Part B), offering participants the option to unblind and for placebo recipients to receive mRNA-1273. The protocol was further amended to offer a 50-µg booster dose of mRNA-1273 to coincide with its authorization in October 2021,²⁸ to all vaccinated participants in the study (Part C). Herein, the final efficacy and safety results of the open-label and booster Parts (B and C) of the trial through study-end are reported.

Trial Population

A total of 29,036 participants started open-label Part B including those who had received mRNA-1273 (mRNA-1273 group) or placebo in Part A and crossed-over (placebo-mRNA-1273 group) to receive at least 1 injection of mRNA-1273 in Part B, and placebo participants who continued the study and did not receive mRNA-1273 in Part B (Fig. 1). In Part C, 9,647 participants in the mRNA-1273 and 9,952 in the cross-over placebo-mRNA-1273 groups received the booster. Safety was assessed in 30,346 participants for the primary vaccine series and 19,609 participants for the booster and efficacy in 28,463 and 16,368 participants, respectively (Fig. S2). Immunogenicity was evaluated in 731 participants in the mRNA-1273 group in the per-protocol immunogenicity set (PPIS) (Figs. S2-S3).

Baseline characteristics of the Part C-booster participants were generally balanced and similar to those of the blinded, Part A COVE study cohort^1,2 (Table S5). Prior SARS-CoV-2-infection was present in 198 (2.1%) and 184 (1.8%) of participants at baseline in Part A, and 941 (9.8%) and 1647 (16.5%) at pre-booster in the mRNA-1273 and placebo-mRNA-1273 groups, respectively. Median follow-up times (interquartile ranges [IQRs]) were 392 (373–413) and 250 (236–266) days between the second-injection of the primary series to the booster and 333 (309–357) and 325 (299–351) days post-booster follow-up to study end for the mRNA-1273 and placebo-mRNA-1273 groups respectively.

Safety

The median follow-up measured in days (IQR) for the primary series between the first injection of the primary series and the booster administration date, or last date of study participation or study-end, whichever was earliest, was 415 (386–442) in the mRNA-1273 and 281 (266–302) in the placebo-mRNA-1273 groups. Safety was similar to that previously reported for the blinded part of the study^1,2 and post-authorization data with no new safety concerns identified in either group (Tables S6-S8).

Among the 19,609 booster recipients, 34.2% of participants in the mRNA-1273 group and 31.6% in the placebo-mRNA-1273 group experienced adverse events (AEs) ≤ 28 days after the booster dose (Table S9). Of these participants, 25.1% in the mRNA-1273 group and 21.8% in the placebo-mRNA-1273 group had AEs considered by the investigator to be vaccine-related; most were consistent with the known reactogenicity of the vaccine (Table S10). Serious AEs considered by the investigator to be vaccine-related occurred in 3 [< 0.1%] participants in the mRNA-1273 group including a case of myocarditis that occurred on day 1 post-booster that resolved at day 72 in a participant aged > 40 years who had just completed treatment for an upper respiratory infection one month prior; a case of coronary arteriospasm with onset on day 11 post-booster in a participant > 70 years of age with known coronary artery disease; and a case of “heart flutter” (not verified by electrocardiogram) with onset on day 12 post-booster in a participant > 40 years of age being treated for anxiety that resolved without treatment the following day (Table S11). One (< 0.1%) serious AE of erythema nodosum occurred in a participant in the placebo-mRNA-1273 group on day 9 post-booster that resolved without treatment on day 30. Fatal AEs were experienced by 6 participants in the booster part of the study; none were considered by the investigator to be vaccine-related. Incidences of AEs ≤ 28 days after the booster, including those considered by the investigator to be related to study vaccine, were generally similar regardless of pre-booster SARS-CoV-2-infection status, sex, race, and ethnicity (Table S13-16). As expected, the frequency of SAEs was higher in older participants (≥ 65 years) compared to younger (≥ 18-<65 years) participants (Table S17).

Adverse events that occurred after the booster dose and up to study-end were reported in 65.4% total participants including 23.6% events considered by the investigator to be related to study vaccine (Table S12). A total of 50 (0.3%) fatal AEs occurred as of study-end; none were attributed to study vaccine. Four deaths were associated with COVID-19, two during Part B and two after booster in Part C.

Efficacy

Among 1055 COVID-19 cases that occurred in the study prior to the booster dose, Delta (46.1%) and Omicron BA.1 (16.2%) were the most frequently detected variants (Table S19). Among 3,538 COVID-19 cases that occurred following the booster dose, Omicron variants were the most frequently-detected variants (75.0%) including subvariants BA.1 (1109 [31.3%), BA.2 (744 [21.0%]), BA.4 (144 [4.1%]) and BA.5 (647 [18.3%]). Results were similar for severe adjudicated COVID-19 cases.

Primary series vaccination

Overall, in both groups combined, quarterly COVID-19 incidence (95% confidence intervals [CIs]) per 1,000 person-months detected 14 days after injection 2 of the primary series were low, starting January 1, 2021 (0.9 [0.66–1.2]) in Part B of the trial then increased from July 1, 2021 to September 30, 2021 (8.35 [7.67–9.08]) coinciding with the Delta surge¹⁵, with the highest incidences observed starting after December 31st, 2021 (61.72 [52.89–71.60]) during the Omicron waves (Table S20). The majority of COVID-19 cases for the primary series occurred when Omicron BA.1 was predominant compared with Delta and Omicron BA.2, BA.4/5 and BQ1.1 variants (Table 1). Overall incidence starting 14 days following injection two of the primary series through April 7, 2023 were similar in the mRNA-1273 and placebo-mRNA-1273 groups for COVID-19 cases defined per the Centers for Disease Control and Prevention guidelines²⁹ and prior SARS-CoV-2-infection regardless of symptomatology and severity (Table S21).

Table 1

Analysis of COVID-19 and severe COVID-19 incidence based on Adjudication Committee assessments starting 14 days after injection 2 of mRNA-1273 100-µg primary series prior to the booster, by variant waves (PP-Primary Series Set)
	COVID-19 Cases		Severe COVID-19 Cases
	mRNA-1273 100 µg Primary Series	Placebo- mRNA-1273 100 µg Primary Series	mRNA-1273 100 µg Primary Series	Placebo- mRNA-1273 100 µg Primary Series
	N = 14291	N = 10623	N = 14291	N = 10623
September 1, 2021-November 30, 2021 (Delta predominant)
Number at risk (N1)	11436	10020	11751	10179
Participants with event, n (%)^a	159 (1.4)	113 (1.1)	27 (0.2)	15 (0.1)
Person-months^b	20488.2	19620.5	21388.1	20112.0
Incidence/1,000 person- months (95% CI)^c	7.76 (6.60–9.07)	5.76 (4.75–6.92)	1.26 (0.83–1.84)	0.75 (0.42–1.23)
December 1, 2021-March 31, 2022 (Omicron BA.1 predominant)
Number at risk (N1)	1648	1610	1816	1714
Participants with event, n (%)^a	127 (7.7)	107 (6.6)	8 (0.4)	5 (0.3)
Person-months^b	2817.0	2230.5	3343.3	2614.6
Incidence/1,000 person- months (95% CI)^c	45.08 (37.58–53.64)	47.97 (39.31–57.97)	2.39 (1.03–4.72)	1.91 (0.62–4.46)
April 1, 2022-June 30, 2022 (Omicron BA.2 predominant)
Number at risk (N1)	399	271	506	356
Participants with event, n (%)^a	14 (3.5)	5 (1.8)	1 (0.2)	0
Person-months^b	1120.3	719.8	1437.4	976.2
Incidence/1,000 person- months (95% CI)^c	12.50 (6.83–20.97)	6.95 (2.26–16.21)	0.70 (0.02–3.88)	0.00 (NE-3.78)
July 1, 2022-November 30, 2022 (Omicron BA.4/5 predominant)
Number at risk (N1)	349	220	459	308
Participants with event, n (%)^a	8 (2.3)	12 (5.5)	0	0
Person-months^b	1081.6	672.1	1407.2	940.1
Incidence/1,000 person- months (95% CI)^c	7.40 (3.19–14.57)	17.85 (9.23–31.19)	0.00 (NE-2.62)	0.00 (NE-3.92)
December 1, 2022-April 7, 2023 (Omicron BQ.1.1 predominant)
Number at risk (N1)	38	31	41	34
Participants with event, n (%)^a	0	0	0	0
Person-months^b	28.6	16.8	31.1	18.2
Incidence/1,000 person- months (95% CI)^c	0.00 (NE-128.91)	0.00 (NE-220.16)	0.00 (NE-118.69)	0.00 (NE-203.04)
CI, confidence interval; NE, not estimable. Incidence based on COVID-19 and severe COVID-19 cases adjudicated by an independent adjudication committee to determine if the criteria for the efficacy endpoints were met. COVID-19 is based on adjudicated cases as assessed in the primary approach for COVID-19 throughout the study. Per-Protocol Primary Series Set includes participants in Part A Per-Protocol Set who received two doses of mRNA-1273 primary series in either Parts A or Part B per schedule without major protocol deviations. ^a Percentages are based on N1. ^b Person-months for each time period is defined as the total months from the start of each time period or 14 days after the date of injection 2 of mRNA-1273 100 µg Primary Series, whichever is later, to the date of event, one day before the date of booster if received, the end of each time period, last date of study participation, or efficacy data-cutoff date, whichever is the earliest. 1 month = 30.4375 days. ^c Incidence for each time period is defined as the number of participants with an event during the time period divided by the number of participants at risk during the time period and adjusted by person-months (total time at risk) in each treatment group. The 95% CI is calculated using the exact method (Poisson distribution) and adjusted by person-months.

Booster vaccination

Among 16,368 boosted participants, COVID-19 disease incidence (95% CI per 1000 person-months) starting at 14 days post-booster was lower in the mRNA-1273 group than the placebo-mRNA-1273 group (25.43 [24.25–26.65] and 29.83 [28.46–31.24]), respectively. Severe COVID-19 disease incidence was similar in the two groups (1.10 [0.87–1.36] and 1.21 [0.96–1.50] respectively) (Table 2). Most COVID-19 and severe COVID-19 incidences following the booster were detected during the Omicron BA.1, BA.2 and BA.4/5 variant waves and were highest during the BA.4/BA.5 wave. Among the 167 severe COVID-19 cases, only 1 participant was hospitalized due to COVID-19. Incidences of COVID-19 starting 14 days post-booster in the mRNA-1273 and placebo-mRNA-1273 groups, respectively, were higher in those initially pre-booster SARS-CoV-2-negative (25.65 [24.48–26.86] and 29.50 [28.17–30.88]) than those SARS-CoV-2-positive (17.02 [10.09–26.90]) and 12.05 [6.41–20.60]), as were those for severe COVID-19 (1.11 [0.89–1.37] and 1.23 [0.99–1.52) vs 0.86 [0.02–4.81] and 0.00 [NE-3.22], respectively) (Tables 3 and S22). Incidences of COVID-19 (Fig. 2) were generally consistent among subgroups and were higher for younger (≥ 18-<65 years) than older (≥ 65 years) participants, Hispanic/Latino versus non-Hispanic/Latino participants and male versus female participants. Incidences of severe COVID-19 were also similar across subgroups with higher incidences for male versus female participants and white participants versus those in communities of color (Fig. S4).

Table 2

Analysis of COVID-19 and severe COVID-19 incidence based on Adjudication Committee assessments starting 14 days after booster, by variant waves (Part C PP Set)
	Part C Booster mRNA-1273 50 µg
	COVID-19 Cases		Severe COVID-19 Cases
	mRNA-1273 100 µg Primary Series	Placebo- mRNA-1273 100 µg Primary Series	mRNA-1273 100 µg Primary Series	Placebo- mRNA-1273 100 µg Primary Series
	N = 8500	N = 7868	N = 8500	N = 7868
≥ 14 days after booster
Number at risk (N1)	8238	7733	8259	7747
Participants with event, n (%)^a	1747 (21.2)	1791 (23.2)	84 (1.0)	83 (1.1)
Person-months^b	68702.2	60045.3	76745.4	68753.6
Incidence/1,000 person- months (95% CI)^c	25.43 (24.25–26.65)	29.83 (28.46–31.24)	1.10 (0.87–1.36)	1.21 (0.96–1.50)
September 1, 2021-November 30, 2021 (Delta predominant)
Number at risk (N1)	7023	6260	7027	6265
Participants with event, n (%)^a	5 (< 0.1)	5 (< 0.1)	1 (< 0.1)	0
Person-months^b	6543.8	5634.6	6547.4	5641.7
Incidence/1,000 person- months (95% CI)^c	0.76 (0.25–1.78)	0.89 (0.29–2.07)	0.15 (0.00-0.85)	0.00 (NE-0.65)
December 1, 2021-March 31, 2022 (Omicron BA.1 predominant)
Number at risk (N1)	8212	7711	8237	7730
Participants with event, n (%)^a	672 (8.2)	801 (10.4)	36 (0.4)	39 (0.5)
Person-months^b	29932.4	27061.7	31468.9	28930.5
Incidence/1,000 person- months (95% CI)^c	22.45 (20.79–24.21)	29.60 (27.58–31.72)	1.14 (0.80–1.58)	1.35 (0.96–1.84)
April 1, 2022-June 30, 2022 (Omicron BA.2 predominant)
Number at risk (N1)	7264	6339	7922	7116
Participants with event, n (%)^a	579 (8.0)	558 (8.8)	25 (0.3)	26 (0.4)
Person-months^b	18401.8	15895.4	20836.6	18615.0
Incidence/1,000 person- months (95% CI)^c	31.46 (28.95–34.14)	35.11 (32.25–38.14)	1.20 (0.78–1.77)	1.40 (0.91–2.05)
July 1, 2022-November 30, 2022 (Omicron BA.4/5 predominant)
Number at risk (N1)	5233	4411	6353	5604
Participants with event, n (%)^a	491 (9.4)	427 (9.7)	22 (0.3)	18 (0.3)
Person-months^b	13758.7	11413.5	17808.1	15509.5
Incidence/1,000 person- months (95% CI)^c	35.69 (32.60-38.99)	37.41 (33.95–41.13)	1.24 (0.77–1.87)	1.16 (0.69–1.83)
After December 1, 2022 (Omicron BQ.1.1 Predominant)
Number at risk (N1)	129	88	171	121
Participants with event, n (%)^a	0	0	0	0
Person-months^b	65.5	40.2	84.5	56.9
Incidence/1,000 person- months (95% CI)^c	0.00 (NE-56.34)	0.00 (NE-91.66)	0.00 (NE-43.67)	0.00 (NE-64.79)
CI, confidence interval; NE, not estimable. Incidence based on COVID-19 and severe COVID-19 cases adjudicated by an independent adjudication committee to determine if the criteria for the efficacy endpoints were met. COVID-19 based on adjudicated assessments are as in the primary approach for COVID-19 throughout the study. Part C per-protocol set consisted of all participants who were randomized in part A, received mRNA-1273 50-ug booster in part C after primary series per schedule (within [21–42] days after injection 1), were pre-booster SARS-CoV-2-negative and had no major protocol deviations that impact critical or key data. Part C PP Set used for analysis of efficacy of booster. ^a Percentages are based on N1. ^b Person-months for each time period is defined as the total months from the start of each time period or the date of booster, whichever is later, to the date of event, the end of each time period, last date of study participation, or efficacy data-cutoff date, whichever is the earliest. 1 month = 30.4375 days. ^c Incidence for each time period is defined as the number of participants with an event during the time period divided by the number of participants at risk during the time period and adjusted by person-months (total time at risk) in each treatment group. The 95% CI is calculated using the exact method (Poisson distribution) and adjusted by person-months.

Table 3

Analysis of COVID-19 incidence based on Adjudication Committee assessments starting 14 days after booster, by pre-booster SARS-CoV-2 status (Part C Safety Set)
	Part C Booster mRNA-1273 50 µg
	mRNA-1273 100 µg Primary Series^a	Placebo-mRNA-1273 100 µg Primary Series		mRNA-1273 100 µg Primary Series^a	Placebo-mRNA-1273 100 µg Primary Series
	Negative (n = 8705)	Negative (n = 8305)		Positive (n = 941)	Positive (n = 1647)
≥ 14 days after booster
Number at risk (N1)	8431	8031		120	119
Participants with event, n (%)^a	1802 (21.4)	1845 (23.0)		18 (15.0)	13 (10.9)
Person-months^b	70251.6	62537.2		1057.6	1079.1
Incidence/1,000 person- months (95% CI)^c	25.65 (24.48–26.86)	29.50 (28.17–30.88)		17.02 (10.09–26.90)	12.05 (6.41–20.60)
September 1, 2021-November 30, 2021 (Delta predominant)
Number at risk (N1)	7175	6497		92	98
Participants with event, n (%)^a	6 (< 0.1)	5 (< 0.1)		0	0
Person-months^b	6688.5	5840.7		78.8	78.7
Incidence/1,000 person- months (95% CI)^c	0.90 (0.33–1.95)	0.86 (0.28-2.00)		0.00 (NE-46.80)	0.00 (NE-46.88)
December 1, 2021-March 31, 2022 (Omicron BA.1 predominant)
Number at risk (N1)	8404	8005		115	119
Participants with event, n (%)^a	699 (8.3)	823 (10.3)		9 (7.8)	5 (4.2)
Person-months^b	30589.4	28103.2		399.6	424.0
Incidence/1,000 person- months (95% CI)^c	22.85 (21.19–24.61)	29.29 (27.32–31.36)		22.52 (10.30-42.76)	11.79 (3.83–27.52)
April 1, 2022-June 30, 2022 (Omicron BA.2 predominant)
Number at risk (N1)	7425	6595		106	106
Participants with event, n (%)^a	590 (7.9)		577 (8.7)	3 (2.8)	3 (2.8)
Person-months^b	18829.2		16582.4	302.8	293.9
Incidence/1,000 person- months (95% CI)^c	31.33 (28.86–33.97)		34.80 (32.01–37.76)	9.91 (2.04–28.96)	10.21 (2.11–29.83)
July 1, 2022-November 30, 2022 (Omicron BA.4/5 predominant)
Number at risk (N1)	5357		4617	95	92
Participants with event, n (%)^a	507 (9.5)		440 (9.5)	6 (6.3)	5 (5.4)
Person-months^b	14077.1		11968.3	273.9	280.8
Incidence/1,000 person- months (95% CI)^c	36.02 (32.95–39.29)		36.76 (33.41–40.37)	21.90 (8.04–47.67)	17.80 (5.78–41.55)
After December 1, 2022 (Omicron BQ.1.1 Predominant)
Number at risk (N1)	135		95	3	2
Participants with event, n (%)^a	0		0	0	0
Person-months^b	67.5		42.6	2.5	1.6
Incidence/1,000 person- months (95% CI)^c	0.00 (NE-54.66)		0.00 (NE-86.57)	0.00 (NE-1477.37)	0.00 (NE-2245.61)
CI, confidence interval; NE, not estimable. ^a Two participants from mRNA-1273 group had a missing pre-booster SARS-CoV-2-status. ^b Percentages are based on N1. ^c Person-months for each time period is defined as the total months from the start of each time period to the date of event, the end of each time period, last date of study participation, or efficacy data-cutoff date, whichever is the earliest. 1 month = 30.4375 days. ^d Incidence for each time period is defined as the number of participants with an event during the time period divided by the number of participants at risk during the time period and adjusted by person-months (total time at risk) in each treatment group. The 95% CI is calculated using the exact method (Poisson distribution) and adjusted by person-months.

Booster receipt versus no booster was associated with relative reductions (95% CI) of 76.3% (65.7–84.1%) and 47.0% (39.0-53.9%) of COVID-19 incidences during the Delta and Omicron BA.1 waves, respectively (Table 4). The low number of non-boosted participants at risk limited evaluation in subsequent omicron waves.

Table 4

COVID-19 incidence based on Adjudication Committee assessments by variant waves for booster and non-booster participants (PP-Primary Series Set)
	COVID-19		Severe COVID-19
	Booster mRNA-1273 50 µg N = 17657^a	Non-Booster N = 7257^a	Booster mRNA-1273 50 µg N = 17657^a	Non-Booster N = 7257^a
September 1, 2021-November 30, 2021 (Delta predominant)
Participants at Risk (N1)	15557	21456	15557	21930
Participants with Event, n (%)^b	32 (0.2)	272 (1.3)	2 (< 0.1)	42 (0.2)
Person-Months^c	19874.5	40108.7	19900.3	41500.1
Incidence/1,000 Person-Months^d	1.61 (1.10–2.27)	6.78 (6.00- 7.64)	0.10 (0.01–0.36)	1.01 (0.73–1.37)
Incidence Reduction, % (95% CI)^e	76.3 (65.7–84.1)		90.1 (61.8–98.8)
December 1, 2021-March 31, 2022 (Omicron BA.1 predominant)
Participants at Risk (N1)	17549	3258	17579	3530
Participants with Event, n (%)^b	1553 (8.8)	234 (7.2)	79 (0.4)	13 (0.4)
Person-Months^c	63229.6	5047.5	66803.2	5957.9
Incidence/1,000 Person-Months^d	24.56 (23.36–25.81)	46.36 (40.61–52.70)	1.18 (0.94–1.47)	2.18 (1.16–3.73)
Incidence Reduction, % (95% CI)^e	47.0 (39.0-53.9)		45.8 (-6.3-70.1)
April 1, 2022-June 30, 2022 (Omicron BA.2 predominant)
Participants at Risk (N1)	15044	670	16541	862
Participants with Event, n (%)^b	1181 (7.9)	19 (2.8)	52 (0.3)	1 (0.1)
Person-Months^c	38329.6	1840.1	43691.6	2413.6
Incidence/1,000 Person-Months^d	30.81 (29.08–32.62)	10.33 (6.22–16.12)	1.19 (0.89–1.56)	0.41 (0.01–2.31)
Incidence Reduction, % (95% CI)^e	-198.4 (-397.4 to -90.2)		-187.3 (-11461.5-50.7)
July 1, 2022-November 30, 2022 (Omicron BA.4/5 predominant)
Participants at Risk (N1)	10884	569	13294	767
Participants with Event, n (%)^b	969 (8.9)	20 (3.5)	41 (0.3)	0
Person-Months^c	28660.7	1753.7	37188.3	2347.3
Incidence/1,000 Person-Months^d	33.81 (31.71–36.01)	11.41 (6.97–17.61)	1.10 (0.79–1.50)	0.00 (NE-1.57)
Incidence Reduction, % (95% CI)^e	-196.5 (-387.5 to -90.9)		NE (NE-NE)
After December 1, 2022 (Omicron BQ.1.1 predominant)
Participants at Risk (N1)	268	69	348	75
Participants with Event, n (%)^b	1 (0.4)	0	0	0
Person-Months^c	127.9	45.4	165.2	49.2
Incidence/1,000 Person-Months^d	7.82 (0.20-43.57)	0.00 (NE-81.30)	0.00 (NE-22.34)	0.00 (NE-74.90)
Incidence Reduction, % (95% CI)^e	NE (NE-NE)		NE (NE-NE)
CI, confidence interval; COVID-19, coronavirus disease 2019; NE, not estimable. For N1 in each time period, a participant who received a booster was included in the non-booster column for the period(s) before booster, and in the booster column for the period(s) after booster. For participants with event(s) before booster and event(s) after booster, the first event after the first injection of the mRNA-1273 100-µg primary series and before booster is counted in the non-booster column; and the first event after booster is counted in the booster column. Participants who received a booster after the primary series were compared with those who had not received a booster after the primary series during the time period. The comparison of incidence rates between booster and non-booster participants and interpretation of this analysis is limited as these groups were not randomized; thus, background IRs could be potentially inconsistent across these groups and direct comparisons may be confounded. ^aN in the header presents total number of participants receiving a booster or not receiving a booster as of data-cutoff date. Participants who received a booster before the end of study participation or data-cutoff date are included in the booster group; otherwise, participants are included in the non-booster column. ^b Percentages based on N1. For N1, participants who received a booster are included in the non-booster column for the period(s) pre- and post-booster. For participants with event(s) pre- and post-booster, the first event after the first injection of the mRNA-1273 100-µg primary series and before booster is counted in the non-booster column; and the first event after booster is counted in the booster column. ^cFor the booster column, person-months is defined as the total months from the start of each time period or the date of booster, whichever is later, to the date of first event after booster, the end of each time period, last date of study participation, or efficacy data-cutoff date, whichever is the earliest. For the non-booster column, person-months for each time period is defined as the total months from the start of each time period to the date of first event after the first injection of mRNA-1273 100-µg primary series, the end of each time period, last date of study participation, or efficacy data-cutoff date, (or one day pre-booster date if received), whichever is the earliest. ^dIncidence for each time period is defined as the number of participants with an event during the time period divided by the number of participants at risk during the time period and adjusted by person-months (total time at risk) in each treatment group. 95% CI is calculated using the exact method (Poisson distribution) and adjusted by person-months. ^eReduction in incidence rate is defined as 1 – ratio of incidence rate (booster vs. non-booster) and 95% CI of the ratio was calculated using the exact method conditional upon the total number of cases, adjusting for person-months for the time period.

Immunogenicity

Following the primary series, neutralizing antibody (nAb) geometric mean concentrations (GMCs) against SARS-CoV-2 (D614G) decreased by day 209 post-vaccination, but remained detectable over a median ~ 13 months follow-up prior to BD-1 (Fig. S5). The booster dose increased nAb GMCs at BD-29 with geometric mean fold-rises (GMFRs) of 842- and 59-fold from pre-vaccination and pre-booster levels, respectively in the PPIS-negative participants (Tables 5, S24-S25 and Fig. S6). The seroresponse rates (SRRs) at BD-29 versus day 57 after the primary series were > 98% (Table 5). Both the GMR and SRR differences exceeded the prespecified superiority criteria for immunogenicity of the booster compared with the primary series. These findings were irrespective of prior SARS-CoV-2-infection. Among participants with evidence of prior SARS-COV-2 infection in the PPIS-set, GMFRs were 1907 from pre-vaccination levels and 3.2 from pre-booster levels (Tables S24-25). Post-booster GMCs decreased by day 181 but remained higher than pre-booster levels for ≥ 6 months regardless of pre-booster SARS-CoV-2-infection status (Fig. S5) and age (Fig. S7). Increases in nAb titers were generally comparable regardless of sex and age; although post-booster increases in GMC from pre-booster baseline levels at day 29 were higher in SARS-CoV-2-negative participants ≥ 65 than those 18–65 years of age (Tables S26-S27). Results for spike binding (bAb) were similar to those of nAb (Tables S28-S29 and Fig. S8).

Table 5

Pseudovirus neutralizing antibody against SARS-CoV-2 (D614G) in booster Part C (BD-29 vs. Part A day 57) Per-Protocol Immunogenicity subset
	PPIS-negative (N = 682)		PPIS-All participants (N = 731)
	mRNA-1273 100 µg Primary Series BD-29	mRNA-1273 100 µg Primary Series Day 57	mRNA-1273 100 µg Primary Series BD-29	mRNA-1273 100 µg Primary Series Day 57
BD Day 29
n	638	680	678	728
GMC (95% CI)^a	7739.7 (7240.93-8272.79)	1111.3 (1041.68-1185.51)	8130.9 (7611.70-8685.60)	1111.0 (1043.75-1182.52)
GMFR (vs pre-vaccination GMC^b) (95% CI)	841.7 (779.0-909.4)	119.4 (110.7-128.7)	882.4 (817.4-952.6)	119. 1 (110.7-128.1)
GMFR (vs pre-booster GMC^b) (95% CI)	59.1 (54.6–64.1)	NA	50.2 (45.6–55.1)	NA
GMR (BD-29 vs. Day 57 GMC) (95% CI)^c	7.0 (6.51–7.52)		7.37 (6.87–7.91)
SRR from pre-vaccination (n/N1, %) (95% CI)^d	636/636, 100 (99.4–100.0)	672/680, 98.8 (97.7–99.5)	675/675, 100 (99.5–100.0)	720/728, 98.9 (97.8–99.5)
SRR difference (BD day 29 vs Day 57) (95% CI)^e	0.9 (0.1–1.8)		0.9 (0.1–1.7)
BD Day 181
n	575		610
GMC (95% CI)	2872.1 (2625.2-3142.2)	-	2951.1 (2701.65-3223.64)	-
GMFR (vs pre-vaccination GMC^b) (95% CI)	305.9 (277.3-337.4)		314.3 (285.4-346.1)
GMFR (95% CI) (vs pre-booster GMC^b)	21.3 (19.2–23.6)	-	17.9 (16.0- 20.2)	-
Day 209
n	-	641	-	684
GMC (95% CI)		237.4 (221.9–254.0)		238.2 (222.6–255.0)
GMFR (95% CI)	-	25.8 (23.8–27.9)	-	25.7 (23.8–27.9)
BD, booster dose; CI, confidence interval; GMC, geometric mean concentration; GMFR, geometric mean fold rise (post-baseline/baseline); GMR, geometric mean ratio; LLOQ, lower limit of quantification; NA, not applicable; RT-PCR, reverse transcriptase polymerase chain reaction (test); SRR, seroresponse rate; ULOQ, upper limit of quantification.. Immunogenicity was assessed by pseudovirus neutralizing antibody assay against SARS-CoV-2 (D614G) in the Part C per-protocol immunogenicity set (PPIS). The primary analysis comparison of immune responses after the booster and primary series of mRNA-1273 was performed in the PPIS-negative set which consists of participants in the PPIS who are pre-booster SARS-CoV-2 negative (no virologic [RT-PCR at BD-Day 1] or serologic evidence [anti-SARS-CoV-2 nucleocapsid on/before BD-Day 1, Roche Elecsys) of SARS-CoV-2 infection. N = Number of participants with non-missing data at the corresponding timepoint. Antibody values reported as below the lower limit of quantification (LLOQ = 10) are replaced by 0.5 x LLOQ. Values greater than the upper limit of quantification (ULOQ = 281,600) are replaced by the ULOQ if actual values are not available. ^a95% CI is calculated based on the t-distribution of the log-transformed values for GMC and GMFR, then back transformed to the original scale for presentation. 95% CI is calculated using the Clopper-Pearson method. ^bGMC (95% CI) are 9.33 (8.95–9.73) at pre-vaccination (day 1) and 164.74 (148.69-182.52) at pre-booster (booster day 1). ^cThe log-transformed antibody levels are analyzed using paired t-test method with the group variable and 95% CI is calculated based on the t-distribution of the mean of paired difference in the log-transformed values, then back transformed to the original scale for presentation. ^dSeroresponse at a participant level is defined as a change from below the LLOQ to equal or above 4 x LLOQ, or at least a 4-fold rise if baseline (Pre injection 1) is equal to or above the LLOQ. 95% CI is calculated using the Clopper-Pearson method. ^eDifference in seroresponse rate and 95% CI is calculated using adjusted Wald method for the paired binary data. The number of participants included in the comparison could be different from N1.

An analysis of pre-booster PPIS-negative participants in the mRNA-1273 group showed that nAb levels and GMFR (BD-1 to BD-29) remained generally consistent regardless of time interval (12–16 months) between second injections of mRNA-1273 and booster doses (Fig. S9). In SARS-CoV-2-positive participants at pre-booster, GMCs increased and GMFR decreased with longer-time intervals. An analysis in a subset (n = 80) of the placebo-mRNA-1273 group showed generally similar results (Fig. S10 and Table S30).

Exploratory Analyses

Booster efficacy was further explored in a Cox model analysis of ~ 20,000 participants in the PP-primary set who remained on study and had no COVID-19 cases by the first booster date (September 23, 2021) of the trial (Fig. S11).³⁰ The proportions of participants who received a booster was 60% for those who received a primary series vaccination by October 31, 2021, 88% by November 30, 2021 and 97% by December 31, 2021 (Fig. S12). Baseline characteristics of the analysis population adjusted by booster timing were generally balanced and similar to those of the overall study population (Table S31). Boosting reduced COVID-19 risk similarly in the mRNA-1273 and placebo-mRNA-1273 arms during the Delta and Omicron waves with hazard ratios (95% CI) of 1.24 (0.91 − 1.70) and 0.91 (0.69 − 1.22) for the pre-boost and 0.86 (0.44 − 1.67) and 0.76 (0.68 − 0.84) for the post-boost periods (Table S32). This corresponded to risk reductions for the mRNA-1273 versus placebo-mRNA-1273 arm of 14% against Delta and 24% against Omicron during longer dosing intervals between 2nd injection and booster for mRNA-1273 (median, 13 months) than placebo-mRNA-1273 (median, 8 months). In both arms, booster efficacy (95% CI) was 83% (60%−93%) against Delta and remained generally stable over 60 days at 83% (67%-91%) regardless of time between 2nd injection of the primary series and booster dose. Against Omicron BA.1, booster efficacy (95% CI) was 56% (44%−65%) immediately post-booster, then decreased to 4% (-27%−28%) over the next 120 days (Fig. S13). In participants ≥ 65 years, booster relative efficacy against Omicron BA.1 decreased from 86% (69%−93%) to 28% (-47%−65%) by 120 days and in those < 65 years, decreased from 50% (36%−61%) to 6% (-29%−31%) by 120 days (Fig. S14).

Follow-up of the COVE trial through its study end of April 2023, showed that primary vaccination with two injections of 100-µg mRNA-1273 induced immune responses against SARS-CoV-2 which were persistent through 13 months and boosting with a 50-µg dose elicited an immune response superior to that of primary vaccination which remained higher than after primary vaccination for ≥ 6 months. Primary vaccination provided protection against COVID-19 and severe COVID-19 that was durable through the Delta wave and decreased over time during the Omicron BA.1 wave. Booster vaccination significantly reduced disease incidence during both the Delta and Omicron BA.1 waves, but the efficacy decreased over time against Omicron.

The long-term safety of the primary series and booster was consistent with data reported previously for the blinded part of the trial and with subsequently reported post-authorization data.^1,2 The mRNA-1273 vaccine demonstrated an acceptable safety profile and no new safety concerns were identified among participants who received a two-injection 100-µg primary series during the period > 6 months post-vaccination and the 50-µg booster during > 11 months follow-up. ^1,2

Boosting in the study with the original 50-ug mRNA-1273 significantly reduced incidences of COVID-19 and severe COVID-19 in the Delta and Omicron BA.1 waves; however, incidences increased during the later Omicron BA.2 and BA.4/5 waves. Adjustment for time-varying effects in an exploratory model showed that boosting extended a reduced risk of COVID-19 by 80% through 60 days post-vaccination during the Delta wave, and initially by > 50% against Omicron, but then decreased during the period 120 days post-boost. The decline in efficacy seen over time was likely due to increased immune escape of emerging variants, given that antibody levels remained substantially enhanced after boosting. These findings support the need for boosting to increase protection against emerging variants. Overall, the incidence of clinically severe disease regardless of strain was extremely low, consistent with the benefit of vaccination and booster immunization against severe COVID-19 disease observed in real-world studies.^7–11 Taken together, these data demonstrate the durable reduction of COVID-19 risk associated with primary series vaccination during early variant waves and the benefit of booster immunization, regardless of prior history of SARS-CoV-2 exposure.

The 50-µg mRNA-1273 booster dose induced nAb and bAb immune responses that were greater than those achieved by primary vaccination, regardless of prior SARS-CoV-2-infection. These higher nAb levels are consistent with demonstrated neutralization of variants following immunization with the 50-µg mRNA-1273^14,17–20 and modified monovalent and bivalent boosters updated with closely matching circulating variants.^21–25 Higher nAb following a booster dose has been shown to be related to a greater risk reduction of Omicron BA.1 COVID-19 in a recent correlates of protection analysis of the COVE trial.^31–35

The exploratory model indicated a reduction of Omicron-associated COVID-19 (24%), with longer dosing intervals between primary vaccination and boosting for mRNA-1273 (13 months) versus placebo-mRNA-1273 (8 months).³⁰ Prior studies have also shown that longer-term intervals between vaccination and boosting result in enhanced immune responses and/or vaccine efficacy for COVID-19 and other viral diseases, including an analysis of the COVE trial.^36–39

Boosting efficacy against COVID-19 in the model analysis as well as nAb increases from baseline were greater among SARS-CoV-2-negative participants aged ≥ 65 years than those 18–65 years, consistent with age group effects shown previously,^2,40 noting that higher risk is associated with extended time intervals prior to boosting due to waning of primary vaccination-conferred immunity,^40–44 and that higher numbers of older than younger individuals are likely to be boosted and may be associated with a greater risk of COVID-19 exposure.^40–43 These findings may be useful in setting policy for boost intervals in at risk groups and are in line with risk-based COVID-19 approaches for prioritized vaccination of older adults and other at risk groups.^45,46

The COVE study was conducted amidst the challenging times of the COVID-19 pandemic in a setting of rapidly shifting epidemiology and corresponding study changes such as unblinding and booster phases; nonetheless, this study was key in informing regulatory agencies toward implementation of vaccination and booster immunization strategies. Consequently, study limitations include the unblinding and resulting lack of a control group for the Part C booster phase, the de-randomization that occurred during the study due to the availability of safe and effective vaccines through EUA, which limited direct comparisons of disease incidence across the initial mRNA-1273 and placebo-mRNA-1273 groups. Additionally, comparisons of disease incidence are potentially impacted by the variation in background SARS-CoV-2 variant predominance for these groups and changes in home testing practices as well as relative timing between primary vaccination and booster immunization. Comparison between booster and non-booster participants was limited in later time periods by the fewer number of participants and person-months at risk in the non-boosted group. Interpretation of the effects of vaccination and booster immunization by SARS-CoV-2-infection status was limited by the smaller size of the SARS-CoV-2-positive compared to the SARS-CoV-2-negative group.

The long-term follow-up of the COVE study shows that primary vaccination and boosting with mRNA-1273 provided efficacy and immunogenicity in preventing COVID-19 and severe COVID-19 with acceptable safety, including during emergent variant waves through April 7, 2023, regardless of prior SARS-CoV-2 infection. These results are consistent with the substantial benefits achieved through global vaccination and booster immunization with safe and effective COVID-19 vaccines in controlling the pandemic and restoring lifestyles to pre-pandemic times.^7–10 Continual monitoring of variants and updates of COVID-19 vaccines are essential toward limiting the spread of future SARS-CoV-2 infections and ensuring pandemic-preparedness.

Acknowledgments

We thank the dedicated participants of the COVE trial, the members of the trial team, members of the DSMB (Richard J. Whitley (Chair), University of Alabama School of Medicine; Abdel Babiker, MRC Clinical Trials Unit at University College, London; Lisa Angeline Cooper, Johns Hopkins University School of Medicine and Bloomberg School of Public Health; Susan Smith Ellenberg, University of Pennsylvania; Alan Fix, Vaccine Development Global Program Center for Vaccine Innovation and Access PATH; Marie Griffin, Vanderbilt University Medical Center; Steven Joffe, Perelman School of Medicine, University of Pennsylvania; Jorge Kalil, Clinics Hospital (HC-FMUSP), Universidade de São Paulo, Brazil; Myron M. Levine, University of Maryland School of Medicine; Malegapuru William Makgoba, University of KwaZulu-Natal; Anastasios A. Tsiatis, North Carolina State University; Renee H. Moore, Emory University) and the adjudication committee (Richard J. Hamill (Chair), Baylor College of Medicine; Lewis Lipsitz, Harvard Medical School; Eric S Rosenberg, Massachusetts General Hospital: Anthony Faugno, Tufts Medical Center) for their critical and timely review of the trial data. We also acknowledge the contribution from the mRNA-1273 Product Coordination Team from BARDA (Robert Bruno, Richard Gorman, Holli Hamilton, Gary Horwith, Chuong Huynh, Nutan Mytle, Corrina Pavetto, Xiaomi Tong, and John Treanor), Frank J. Dutko (Moderna consultant) for editorial support and Katherine Kacena for statistical input. Figure development and editorial assistance was provided by Frank Dutko, PhD, Moderna consultant.

Funding

This work was supported in whole or in part with federal funds from the Department of Health and Human Services; Administration for Strategic Preparedness and Response; Biomedical Advanced Research and Development Authority, under Contract No. 75A50120C00034 (Moderna, Inc.). The findings and conclusions herein are those of the authors and do not necessarily represent the views of the Department of Health and Human Services or its components.

Competing Interests

LRB and HMES report grants from NIH and/or NIAID for the conduct of this study; BE, DF, GH, CS, JAW and SDL have nothing to disclose; EJA reports grants from GSK Janssen, MedImmune, Merck, Micron Technology, Pfizer, and Sanofi Pasteur, served as a consultant for Janssen, Medscape, Pfizer and Sanofi Pasteur and as a member of DSMBs for Kentucky Bioprocessing and Sanofi Pasteur; KN reports receiving a grant from Pfizer; JSO and LC report receiving NIH grants; EA, FP, MB, BG, XW, WD, HZ, AD, RD, and JMM report being employees of Moderna, Inc., and may hold stock/stock options in the company. JET is a Moderna, Inc. consultant.

Data Availability Statement

Data associated with this study are provided in the manuscript and/or supplementary materials, and the protocol and statistical analysis plan are provided as supplementary materials. Access to patient-level data and supporting clinical documents by qualified external researchers may be made available upon request and subject to review. A materials transfer and/or data access agreement with the sponsor will be required for accessing shared data. Such requests can be made to Dr. Lindsey Baden, Brigham and Women’s Hospital, Boston, MA 02115, USA.

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Study Design and Oversight

This 3-part, phase 3, observer-blind, randomized, placebo-controlled (Part A) and open-label (Parts B and C) trial was conducted in 99 US sites in adults with no or stable medical conditions as previously described with 2 years of planned follow-up (Fig. S1).^1,2 Parts B and C open-label offered participants an opportunity to receive the primary series (if received placebo in Part A) and booster of mRNA-1273, respectively. This report is through the protocol planned follow-up plus study augmentation with booster vaccination, given the changing response to the pandemic over time. Longer-term safety, efficacy and immunogenicity data from study initiation (July 27, 2020) through the open-label and booster Parts of the study (B and C) (April 7, 2023) are presented.

The trial was conducted in accordance with the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, Good Clinical Practice guidelines. The central Institutional Review Board approved the protocol and consent forms. All participants provided written informed consent.

Study Objectives

The efficacy, safety, and immunogenicity outcomes of the COVE trial were previously reported for the blinded Part A of the study.^1,2,13 Part B of the study provides longer-term safety follow-up and efficacy data following the primary series from unblinding (or participant decision visit [PDV]) to booster dose at day 1 (BD-1). Part C objectives evaluated the safety, efficacy, and immunogenicity of a 50-µg booster dose of mRNA-1273. Part C boosting started in fall 2021 for all study participants when the booster immunization received EUA, thus creating a difference in boosting interval based on initial randomization schema between initial vaccine recipients (mRNA-1273 group received mRNA-1273 July-December 20) and Part B placebo crossover participants (placebo-mRNA-1273 group received the mRNA-1273 primary series December 2020-April 2021).

Safety for the Part A blinded portion of the study was previously reported.^1,2 Safety data for Parts B and C included unsolicited AEs for 28 days after vaccination, and medically-attended (MAAEs), serious (SAEs), and AEs leading to discontinuations. In addition, safety data for Part C included AEs of special interest (AESIs) including hypersensitivity, cardiac events (myocarditis and pericarditis) and vascular events for Part C through study-end. In Part C, adverse reactions (ARs) were not solicited because the reactogenicity of the 50-µg mRNA-1273 booster dose has been found to be similar to that of the second injection of the primary series;¹⁸ ARs that met the criteria for a MAAE, SAE, or leading to discontinuation were recorded.

Efficacy endpoints for the mRNA-1273 primary series and booster were assessed using active surveillance and included COVID-19 (COVE^1,2 and CDC definitions²⁹), severe COVID-19, serologically confirmed SARS-CoV-2 infection or COVID-19 regardless of symptomatology or severity, asymptomatic SARS-CoV-2 infection and death caused by COVID-19 (Supplementary methods). Cases of COVID-19 and severe COVID-19 were adjudicated by an independent committee. Because Part C lacked a placebo comparison group, efficacy was evaluated by a comparison of COVID-19 incidence rates in boosted and unboosted groups, as well as by inferring effectiveness based on a bridging analysis of immune responses post-boost and post-primary series where efficacy was demonstrated.

Part C immunogenicity objectives compared immune responses following the mRNA-1273 booster at day 29 (BD-29) with immunological responses following two-injections of the mRNA-1273 primary series at day 57 to infer booster effectiveness. Neutralizing antibodies (nAb) against SARS-CoV-2 were analyzed using a pseudovirus nAb assay for ancestral SARS-CoV-2 (D614G) and SARS-CoV-2 spike-bAbs using a Mesoscale Discovery (MSD) assay (Supplementary methods).^47,48

Exploratory endpoints included whole genome sequence analysis of SARS-CoV-2 variants from nasopharyngeal samples of participants at illness visits and booster efficacy using a statistical Cox model adjusting for time-varying effects that estimated COVID-19 risk reduction (Supplementary methods).

Statistical Analysis

Safety was assessed for the primary series in the Primary Series Safety Set, comprised of all participants who were randomized in Part A and received at least one-injection of the primary series (mRNA-1273 and placebo-mRNA-1273 groups), and for the booster in the Part C Safety Set consisting of randomized participants who received 50-µg mRNA-1273 booster (Table S1). Summary statistics of unsolicited AEs, SAEs, MAAEs, AEs leading to withdrawal from study participation, and deaths are presented.

The longer-term efficacy of the primary series was assessed in the per-protocol primary series (PP-primary) set consisting of all participants who received the primary vaccination in Parts A or B and had no evidence of prior SARS-CoV-2 infection (negative RT-PCR and nucleocapsid antibody tests) prior to the primary series. COVID-19 incidence prior to boosting in primary series recipients (mRNA-1273 [early] vs placebo-mRNA-1273 [late] vaccination) is presented. Incidence rates of efficacy endpoints (e.g, COVID-19, severe COVID-19, etc.) post-booster were assessed in the Part C-PP set, which included all participants who received the primary series in Parts A or B followed by a booster dose and were pre-booster SARS-CoV-2-infection negative with no major protocol deviations. mRNA-1273 and placebo-mRNA-1273 groups were not combined for efficacy analyses due to differences in time intervals between the primary series and booster dose.

For the primary series and booster, incidence rates based on the number of participants with adjudicated COVID-19 and severe COVID-19 per number at risk adjusted by person-months and 95% confidence interval (CI) (Poisson distribution) are provided by calendar periods corresponding to variant waves (September 1, 2021-November 30, 2021 [Delta]; December 1, 2021-March 31, 2023 [Omicron BA.1]; April 1, 2022-June 30, 2022 [Omicron BA.2]; July 1, 2022-November 30, 2022 [Omicron BA.4/5]; December 1, 2022-April 7, 2023 [Omicron BQ.1.1]), and by time periods for intervals after vaccination (Supplementary methods).

Relative booster efficacy was assessed in participants who received a booster after the primary series versus non-booster participants who did not receive a booster post-primary series based on adjudicated COVID-19 cases starting 14 days after the booster dose in the PP-primary set using a dynamic approach for each treatment group. Participants considered at risk in the non-boosted group were those in the PP-primary set who had not received a booster at the specified time point, and participants considered at risk in the ‘booster’ group were those in the PP-primary set who had received a booster prior to the specified time point. The comparison of incidence between booster and non-booster participants is limited, as these groups were not randomized. Reductions in incidence (1-incidence ratio) and 95% CI were calculated using the exact method conditional upon the total number of cases, adjusting for person-months. Efficacy against COVID-19 was also evaluated by subgroups (e.g., age, randomization risk stratification, sex, race, ethnicity, severe COVID-19 risk factor).

Immunogenicity was assessed in the Part C PPIS. The Part C PPIS consists of a subset of participants randomly selected in the Per-Protocol Random Subcohort for Immunogenicity who received mRNA-1273 in Part A,¹³ were SARS-CoV-2 negative baseline (pre-injection 1) and received a booster in Part C. Geometric mean concentrations for nAb and GM-levels for bAb, GMFRs and SRRs with 95% CIs (Clopper-Pearson) against ancestral SARS-CoV-2 (D614G) are provided at each post-baseline timepoint relative to pre-injection 1 of primary series and pre-booster (BD-1) baseline. Primary series and booster SRRs were defined as titer changes from baseline below the lower limit of quantification (LLOQ) to ≥ 4 × LLOQ, or ≥ 4-fold rise if the baseline is ≥ LLOQ. For the primary immunogenicity objective, GM ratios (GMR) of nAb responses and SRR differences were compared at 28 days post-booster (BD-29) versus the primary series at day 57 (28 days post-injection 2) in Part C PPIS-negative participants (having no virologic/serologic evidence of SARS-CoV-2-infection on/before BD-1) and in all PPIS participants regardless of prior SARS-CoV-2-infection status. Due to the limited size of the PPIS-positive group, immunogenicity was not compared and is summarized. Criteria for non-inferiority were met when the lower bounds of the 95% CIs for the GMRs and SRR differences were > 0.67 and >-10%, respectively. Criteria for superiority were met when the lower bounds of the 95% CIs for the GMRs and SRR differences were > 1 and > 0, respectively. Immunogenicity data at days 209 after the primary series and 181 post-booster in the PPIS participants and by SARS-CoV-2-infection pre-booster status as well as by age group and SARS-CoV-2-infection pre-booster status are also presented. Analyses of the impact of time intervals between the primary series and booster on antibody responses among PPIS-negative mRNA-1273 participants and in a subset of placebo-mRNA-1273 PPIS-negative participants with non-missing time intervals and immunogenicity results at BD-1 were also performed.

Genotypic analysis of variants by whole-genome sequencing was performed on SARS-CoV-2-positive nasopharyngeal swabs collected at illness visits from participants following the primary series and the booster in Part C. Samples were collected from July 2020 (start of Part A) through April 2022 (data-cutoff date date). The number and percentage of cases by variant were summarized.

Booster efficacy was further explored using a Cox proportional hazards model in participants in the PP-primary set who remained on study and were COVID-19-naïve as of 23-September-2021 (first date that participants were boosted); those who did not receive a booster through January 31, 2022 were censored on that date (See details in the Supplementary methods and Fig. S11).³⁰ The model adjusted for baseline factors (e.g., sex, stratification factor for severe COVID-19 risk [≥ 18 years and < 65 years old not at risk, ≥ 18 years and < 65 years old at risk, and ≥ 65 years old], risk score, early unblinding). As boosting was not randomized, the mRNA-1273 and placebo-mRNA-1273 groups were evaluated in terms of boost initiation with a covariate of time since vaccination in the model with early and late boosted participants who received booster before and on or later than 25-October-2021 (median of booster dates). The incidences of symptomatic COVID-19 against Delta and Omicron during the follow-up period from 23-September-2021 through 05-April 2022 was calculated starting at 14 days post-booster; those who acquired COVID-19 during the interval from the booster dose up to 13 days later were censored.

All analyses were conducted using SAS Version 9.4 or higher.

Yes there is potential Competing Interest. LRB and HMES report grants from NIH and/or NIAID for the conduct of this study; BE, DF, GH, CS, JAW and SDL have nothing to disclose; EJA reports grants from GSK Janssen, MedImmune, Merck, Micron Technology, Pfizer, and Sanofi Pasteur, served as a consultant for Janssen, Medscape, Pfizer and Sanofi Pasteur and as a member of DSMBs for Kentucky Bioprocessing and Sanofi Pasteur; KN reports receiving a grant from Pfizer; JSO and LC report receiving NIH grants; EA, FP, MB, BG, XW, WD, HZ, AD, RD, and JMM report being employees of Moderna, Inc., and may hold stock/stock options in the company. JET is a Moderna, Inc. consultant.

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published 29 Aug, 2024

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Long-term safety and efficacy of COVE study open-label and booster phases

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