Safety and immunogenicity of an mRNA-1273 vaccine booster in adolescents

ABSTRACT

Safety, immunogenicity, and effectiveness of an mRNA-1273 50-μg booster were evaluated in adolescents (12–17 years), with and without pre-booster SARS-CoV-2 infection. Participants who had received the 2-dose mRNA-1273 100-µg primary series in the TeenCOVE trial (NCT04649151) were offered the mRNA-1273 50-μg booster. Primary objectives included safety and inference of effectiveness by establishing noninferiority of neutralizing antibody (nAb) responses after the booster compared with the nAb post-primary series of mRNA-1273 among young adults in COVE (NCT04470427). Binding antibody (bAb) responses against SARS-CoV-2 variants of interest and COVID-19 incidence after vaccination were also evaluated. Median boosting interval was 315 days. The mRNA-1273 booster was well-tolerated, with an acceptable safety profile. Relative to pre-booster, nAb geometric mean levels increased after the booster by 17.8-fold and 4.7-fold among pre-booster SARS-CoV-2–negative and –positive participants, respectively. Effectiveness was successfully inferred based on noninferiority of nAb levels from mRNA-1273 booster dose (Day 29) compared with nAb levels after mRNA-1273 primary series (Day 57) among young adults in COVE. Further, the booster increased bAb levels relative to pre-booster baseline against SARS-CoV-2 variants (alpha [B.1.1.7], beta [B.1.351], gamma [P.1], and delta [B.1.617.2]), regardless of pre-booster SARS-CoV-2 status. COVID-19 incidence (cases per 1000 person-months) was lower among boosted (0 cases) than non-boosted (95.766 cases) participants in January 2022, a peak period during the early omicron transmission. In summary, the mRNA-1273 50-μg booster induced robust nAb responses in previously vaccinated adolescents, regardless of SARS-CoV-2 serostatus. Effectiveness was successfully inferred and the booster was well-tolerated, with no new safety concerns identified.

Introduction

Vaccination against SARS-CoV-2 remains an important public health strategy to reduce the burden of COVID-19 and associated sequelae among adolescents. Between March 2020 and June 2023, approximately 1 in 4 hospitalized children and adolescents aged ≤17 years with COVID-19 in the United States have required intensive care unit admission.¹ Upon the emergence of the omicron variant, a shift in the demographics of COVID-19 hospitalizations to adolescent and younger age groups was observed.² Moreover, between August 2021 and July 2022, COVID-19 was the leading cause of death by infectious or respiratory diseases in children and adolescents aged ≤19 years in the United States.³

The mRNA-1273 vaccine (Spikevax; Moderna, Inc., Cambridge, USA) encodes the ancestral SARS-CoV-2 spike protein and was previously authorized in the United States for prevention of COVID-19 in individuals aged ≥6 months.⁴ The 2-dose mRNA-1273 primary series (100 μg) in adolescents aged 12–17 years, authorized based on findings from a phase 2/3 trial (TeenCOVE),^5,6 demonstrated an acceptable safety profile, with comparable immune responses (vs young adults aged 18–25 years) and vaccine efficacy against COVID-19 (vs adults ≥18 years: 93.3%–100.0%) as those observed in the pivotal phase 3 COVE trial.⁷ However, the emergence of the SARS-CoV-2 delta variant led to increased COVID-19 cases, thereby prompting investigation of an mRNA-1273 booster dose in all ages. Initial safety and immunogenicity in adults aged ≥18 years showed that an mRNA-1273 booster dose (50 µg) induced noninferior immune responses to the mRNA-1273 primary series, generating statistically higher antibody titers than after the primary series.⁸ Furthermore, the mRNA-1273 booster increased neutralizing antibodies (nAbs) against the delta⁸ and omicron⁹ variants. Real-world evidence in adults has demonstrated additional benefit from mRNA-1273 booster doses against the earlier omicron BA.1 variant compared with the primary series.¹⁰

Here, we evaluated the safety, immunogenicity, and inferred effectiveness of a homologous booster dose of mRNA-1273 (50 μg) during the peak early omicron period in January 2022 in healthy adolescents in the Part 1C–1 of the TeenCOVE trial. Importantly, we evaluated immunogenicity of a single mRNA-1273 booster dose in adolescents with and without prior SARS-CoV-2 infection.

Materials and methods

Trial design and participants

The blinded phase of the TeenCOVE trial (NCT04649151) has been described previously (Figure S1).⁷ In brief, adolescents aged 12–17 years were randomly assigned 2:1 to the 2-dose mRNA-1273 100-µg primary series or saline placebo 28 days apart. Following authorization of COVID-19 vaccines in adolescents, placebo recipients were offered the mRNA-1273 primary series in an open-label crossover phase. This report describes findings from the open-label booster phase (Part 1C–1), wherein participants were offered a homologous mRNA-1273 50-μg booster ≥5 months after receiving dose 2 of the mRNA-1273 primary series. Homologous booster vaccination refers to a booster that is the same as the primary vaccine series, whereas heterologous booster vaccination refers to a booster that is different from the primary vaccine series.¹¹ Data are summarized from booster dose-Day 1 (first participant first visit) to the data cutoff date (December 27, 2021, to August 15, 2022).

Eligible participants for the booster phase were adolescents aged 12–17 years previously enrolled in TeenCOVE, actively participating in the blinded or open-label phases, and ≥5 months from the last dose of mRNA-1273. Inclusion/exclusion criteria are detailed in the Supplement. Participants in the booster phase were enrolled at 25 sites in the United States.

The protocol, amendments, informed consent form, and all other relevant documents were approved by a central Institutional Review Board (Advarra, Inc). Adolescent (12–17 years) participants’ parent(s)/legally authorized representative(s) or participants reaching the age of majority during the study provided written informed consent to participate in the Part 1C–1 Booster phase. The trial was conducted in accordance with the principles expressed in the Declaration of Helsinki.

Vaccine

mRNA-1273 contains mRNA encoding the prefusion stabilized S protein of SARS-CoV-2 formulated in lipid nanoparticles. The booster was administered intramuscularly into the deltoid muscle (preferably the nondominant arm) at a 0.25-mL volume containing 50 μg of mRNA-1273.

Objectives

The booster phase of the TeenCOVE trial was designed to evaluate the safety, reactogenicity, and effectiveness of mRNA-1273 vaccine administered as a booster dose in the adolescent population. The primary objectives were to evaluate safety and to infer effectiveness of the mRNA-1273 booster by establishing noninferiority (NI) of the antibody responses after the booster in TeenCOVE compared with the antibody response after the mRNA-1273 primary series in young adults in COVE. The secondary objective was to evaluate the immune response elicited by the mRNA-1273 booster against SARS-CoV-2 variants of interest. Immunogenicity of the mRNA-1273 booster was assessed in adolescent participants with and without pre-booster SARS-CoV-2 infection. An exploratory objective was to evaluate the incidence of symptomatic COVID-19 after the mRNA-1273 booster.

Safety assessments

The primary safety endpoints were solicited local and systemic adverse reactions (ARs) through 7 days after vaccination, which were graded using the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventative Vaccine Clinical Trials¹² (Table S1); unsolicited treatment-emergent adverse events (TEAEs) through 28 days after vaccination; medically attended adverse events (MAAEs), serious adverse events (SAEs), and adverse events (AEs) of special interest (AESIs; including multisystem inflammatory syndrome in children [MIS-C]; Table S2) throughout the study; and TEAEs leading to discontinuation from participation after vaccination through the last day of participation. The AESIs selected for analysis were chosen because they might potentially have been related to COVID-19 or were of interest in COVID-19 vaccine safety surveillance.

Immunogenicity assessments

Serum samples for immunogenicity analyses were collected at pre-booster dose-Day 1 and booster dose-Day 29; historical serum samples from young adults (COVE) at baseline (Day 1) and 28 days after dose 2 (Day 57) of the primary series were also evaluated. Pre-booster SARS-CoV-2-positive status was determined by positive reverse transcriptase polymerase chain reaction (RT-PCR) test or positive Elecsys result (measures binding antibody [bAb] against SARS-CoV-2 nucleocapsid protein) at Day 1. Geometric mean concentrations (GMCs) of nAbs against SARS-CoV-2 (D614G strain) were measured using a pseudovirus neutralization assay (VAC62),¹³ with a lower limit of quantification (LLOQ) of 10. bAb geometric means (GMs) specific to the SARS-CoV-2 spike protein (D614G strain as well as alpha [B.1.1.7], beta [B.1.351], gamma [P.1], and delta [B.1.617.2] variants) were measured using a ligand-binding assay (MesoScale Discovery-Electrochemiluminescence Multiplex; VAC113). Omicron-specific bAbs were not measured due to the absence of the BA.1 antigen in the VAC113 assay.

Incidence rates

Symptomatic COVID-19 cases were collected starting 14 days after the booster and were defined using the COVE study case definition (Table S3). Surveillance for COVID-19 symptoms was conducted via safety telephone calls and during clinic visits post booster dose. If fulfilling the prespecified criteria of suspicion for COVID-19 (see Supplement: Surveillance for COVID-19 Symptoms), the participant was asked to return within 72 hours or as soon as possible to the study site for an unscheduled illness visit, which included a nasopharyngeal or nasal swab sample (for RT-PCR testing).

As an additional exploratory analysis, the incidence rate of symptomatic COVID-19 at the peak of the omicron wave in January 2022 was reported among booster and non-booster participants. Beyond January 2022, the rapid decrease in the size of the non-booster group as well as the rapid decline of cases over time severely limited comparisons. Participants from the non-booster group moved into the booster group after meeting the following conditions: (i) receipt of booster dose and (ii) elapsing of 14 days from booster dose administration without a COVID-19 event.

Statistical analyses

All participants enrolled in TeenCOVE who were eligible for the booster phase were offered the mRNA-1273 booster.

Safety analyses were based on the safety set, and solicited AR analyses were based on the solicited safety set. Analysis sets are defined in Table S4. The number and percentage of participants who reported solicited local and systemic ARs and unsolicited TEAEs were summarized; 2-sided 95% exact confidence intervals (CIs) were calculated using the Clopper-Pearson method.

Immunogenicity analyses were conducted using data from the first 400 participants who received the booster, had non-missing SARS-CoV-2 status at baseline, and were randomly assigned to receive mRNA-1273 during the blinded phase (rather than placebo) to provide a population with a more homogenous interval between the primary series and booster. The primary immunogenicity analysis used to infer vaccine effectiveness was based on the per-protocol immunogenicity subset – pre-booster SARS-CoV-2–negative (PPIS-Neg); immunogenicity analyses were also performed in PPIS by pre-booster SARS-CoV-2 status (ie, PPIS-Neg and PPIS–pre-booster SARS-CoV-2–positive [PPIS-Pos]). GMs with 2-sided 95% CIs were summarized using the t-distribution of the log-transformed antibody values and back-transformed to the original scale. Geometric mean ratios (GMRs) with 2-sided 95% CIs were calculated to compare post-booster GMs at booster dose-Day 29 in adolescents in TeenCOVE with the primary series GM at Day 57 (28 days after dose 2) in young adults in COVE; GMRs were computed based on the t-distribution of mean differences in the log-transformed values and back-transformed to the original scale. NI was declared if the lower bound (LB) of the GMR 95% CI was > 0.667 (based on the NI margin of 1.5) and the GMR point estimate was ≥ 0.8 (minimum threshold). Seroresponse rates (SRRs) at booster dose-Day 29 relative to pre-dose 1 in adolescents in TeenCOVE were compared to the primary series SRRs at Day 57 (28 days after dose 2) in young adults in COVE. SRRs were computed using 2-sided 95% Clopper-Pearson CIs, and the SRR differences were calculated with 2-sided 95% CIs using the Miettinen-Nurminen score method. Participant-level seroresponse was defined as antibody measure change from pre-dose 1 below the LLOQ to ≥ 4 × LLOQ, or ≥ 4-fold-rise if pre-dose 1 was ≥LLOQ. NI was demonstrated if the LB of the SRR difference 95% CI was >–10%, based on the NI margin of 10%. Statistical analyses were conducted using SAS software Version 9.4 or higher (SAS Institute, Inc, Cary, NC). Exploratory analyses are described in the Supplement.

Results

Participants

Between December 27, 2021, and August 15, 2022, 1405 adolescents received the mRNA-1273 booster (Figure 1) and were followed for a median of 204 days (range, 1–232 days). Median time (range) between dose 2 of the primary series and the booster was 316 days (274–514) in the mRNA-1273-Booster group and 185 days (63–259) in the Placebo-mRNA-1273-Booster group. The primary immunogenicity analysis only included participants in the mRNA-1273-Booster group. Male participants comprised 51.5% of the study population (723/1405 participants) and the median age was 14.0 years (range, 12–17 years), with 80.1% of participants (1126/1405) aged 12–15 years (Table 1). Before booster administration, 42.5% of participants (597/1405) were SARS-CoV-2 positive (had immunologic or virologic evidence of prior COVID-19).

Figure 1.

Participant disposition.

^aA total of 1405 participants received the mRNA-1273 booster: 1356 from the original mRNA-1273 primary series group and 49 from the original placebo group (participants in the placebo group received the crossover mRNA-1273 primary series in the open-label phase). Of note, following the initial COVID-19 emergency use vaccine authorization in adolescents in May 2021,¹⁴ a substantial number of participants from the blinded phase withdrew to receive vaccination outside of the study, leading to a reduced number of participants enrolled in the open-label booster phase.

^bStudy completion was defined as a participant who completed 12 months of follow-up after the booster dose. This was a site error confirmed after the database lock.

^c“Other” reasons for study discontinuation included the participant’s school schedule interfering with visits, participant receiving a Pfizer COVID booster vaccine, and participant moving to another location and unable to follow up.

^d“Other” reasons for withdrawal of consent included participant moved out of state or moved from area, legally authorized representative withdrew consent, participant no longer wanted to come to the site for visits, participant no longer wanted to participate in the study, the drive to the clinic was too far and gas prices were too high, onsite visits were no longer feasible, participant did not want to do any further blood draws, and unspecified personal reasons.

^e“COVID-19 non-infection related” refers to situations related to pandemic conditions (eg, reluctance to attend study site visits because of concerns regarding SARS-CoV-2 transmissibility) rather than to SARS-CoV-2 infection or COVID-19 in the participant.

EUA, emergency use authorization.

Table 1.

Baseline demographics and other baseline characteristics.

		Booster Phase Participantsa (N = 1405)
Age (years)
	Mean (standard deviation)	14.1 (1.53)
	Median (minimum, maximum)	14.0 (12, 17)
Age group, n (%)
	12–15 years	1126 (80.1)
	16–17 years	279 (19.9)
Sex, n (%)
	Male	723 (51.5)
	Female	682 (48.5)
Race, n (%)
	White	1193 (84.9)
	Black	44 (3.1)
	Asian	69 (4.9)
	American Indian or Alaska Native	7 (0.5)
	Native Hawaiian or Other Pacific Islander	1 (<0.1)
	Multiracial	73 (5.2)
	Other	10 (0.7)
	Not reported	4 (0.3)
	Unknown	4 (0.3)
Ethnicity, n (%)
	Hispanic or Latino	188 (13.4)
	Not Hispanic or Latino	1206 (85.8)
	Not reported	11 (0.8)
Pre-booster SARS-CoV-2 status, n (%)b
	Negative	752 (53.5)
	Positive	597 (42.5)
	Missing	56 (4.0)
Time from primary series (dose 2) to booster dose (days)
	Median, range	315 (63–514)

RT-PCR, reverse transcriptase polymerase chain reaction.

^aParticipants from the safety set.

^bPre-booster SARS-CoV-2 status was categorized as positive if there was immunologic or virologic evidence of prior COVID-19, defined as positive RT-PCR test or positive Elecsys result at booster dose-Day 1 in the booster phase. Pre-booster SARS-CoV-2 status was categorized as negative if there was a negative RT-PCR test and negative Elecsys result at booster dose-Day 1 in the booster phase.

Immunogenicity

A total of 374 participants met the criteria for the Immunogenicity Subset and 327 (87.4%) met the criteria for the PPIS; 47 participants were excluded from the PPIS due to lacking immunogenicity data at Day 1 (n = 5) and Day 29 (n = 28), and due to being SARS-CoV-2 positive prior to dose 1 of the primary series (n = 14). Of the 327 participants in the PPIS, 264 (80.7%) were SARS-CoV-2 negative pre-booster (PPIS-Neg), 51 (15.6%) were SARS-CoV-2 positive (PPIS-Pos), and 12 (3.7%) had missing pre-booster data.

In the primary analysis using PPIS-Neg, nAb GMCs (95% CIs) at 28 days after an mRNA-1273 booster dose were 7102.0 (6553.2–7696.8), an increase of 18-fold (geometric mean fold rise [GMFR], 17.8; 95% CI, 16.1–19.6) relative to pre-booster (booster dose-Day 1 GMC, 398.9; 369.1–431.1; Figure 2). NI of nAb responses after the booster in adolescents relative to after dose 2 (Day 57) of the mRNA-1273 primary series among young adults (18–25 years) was successfully demonstrated, both by 1) a GMR (95% CI) of 5.071 (4.477–5.745) that met the NI criterion (LB of the 95% CI > 0.667) and 2) a difference in SRR (SRR for adolescents, 100%) compared with the young adult SRR of 0.7% (95% CI, −0.8% to 2.4%) that met the NI criterion (LB of the 95% CI >–10%; Table 2). An mRNA-1273 booster dose also induced measurable nAb responses in adolescents with pre-booster infection (n = 51), with an nAb GMC (95% CI) at booster dose-Day 29 of 13456.8 (11061.8–16,370.5), an increase of 5-fold (GMFR, 4.7; 95% CI, 3.3–6.6) relative to pre-booster (booster dose-Day 1 GMC, 2885.6; 1878.2–4433.4). Relative to pre-booster, GM levels of bAbs against ancestral SARS-CoV-2 (D614G) increased 15-fold (GMFR, 14.6; 95% CI, 13.1–16.2) for participants with pre-booster negative SARS-CoV-2 status and 4-fold (GMFR, 4.0; 95% CI, 3.0–5.3) for those with pre-booster positive status. For all SARS-CoV-2 variants of interest (alpha [B.1.1.7], beta [B.1.351], gamma [P.1], and delta [B.1.617.2]), the mRNA-1273 booster led to a robust increase in bAb GMs at booster dose-Day 29 compared with pre-booster levels (booster dose-Day 1; Figure S2) regardless of participant pre-booster SARS-CoV-2 status.

Figure 2.

Neutralizing antibody concentrations against ancestral SARS-CoV-2 (D614G) in adolescent mRNA-1273 booster recipients by pre-booster SARS-CoV-2 status.

Data are representative of the per-protocol immunogenicity set. Antibody values reported below the LLOQ were replaced by 0.5 × LLOQ. Values greater than the ULOQ were replaced by the ULOQ if the actual values were not available. 95% CIs were calculated based on the t distribution of the log-transformed values for GMC, then back-transformed to the original scale for presentation.

CI, confidence interval; GMC, geometric mean concentration; LLOQ, lower limit of quantification; ULOQ, upper limit of quantification.

Table 2.

Serum nAb responses against ancestral SARS-CoV-2 following the mRNA-1273 booster.

	Adolescents 12 to 17 Years mRNA-1273 Booster Dose (n = 264)a	Young Adults 18 to 25 Years mRNA-1273 Primary Series (n = 295)a
Baseline (pre-booster Day 1 or pre-dose 1b), n	264	295
Observed GMC (95% CI)c	398.9 (369.1–431.1)	11.1 (10.5–11.6)
Day 29 post-booster or Day 57 post-primary series, n	264	294
Observed GMC (95% CI)	7102.0 (6553.2–7696.8)	1400.4 (1272.7–1541.0)
GMFR from pre-booster Day 1 (95% CI)c	17.8 (16.1–19.6)	-
GMR vs young adults (95% CI)d	5.1 (4.5–5.7)	-
Day 29 post-booster or Day 57 post-primary SRR, n/N (%) [95% CI]e	264/264 (100) [98.6–100]	292/294 (99.3) [97.6–99.9]
SRR difference vs young adults, % (95% CI)f	0.7 (−0.8 to 2.4)	-

CI, confidence interval; GMC, geometric mean concentration; GMFR, geometric mean fold-rise; GMR, geometric mean ratio; LLOQ, lower limit of quantification; nAb, neutralizing antibody; SRR, seroresponse rate.

Data are representative of the per-protocol immunogenicity, SARS-CoV-2–negative set.

^aNumber of participants in the per-protocol immunogenicity subset with pre-booster SARS-CoV-2–negative status in TeenCOVE, or per-protocol immunogenicity subset in the COVE trial.

^bPre-booster Day 1 in adolescents aged 12–17 years; pre-dose 1 in young adults aged ≥18 and ≤25 years.

^c95% CIs were calculated using the t distribution of the log-transformed values or difference in the log-transformed values, then back-transformed to the original scale for presentation of GMC or GMFR.

^dThe log-transformed antibody levels were analyzed using the t test method, with the group variable (adolescents in TeenCOVE and young adults in COVE); the 95% CI was calculated based on the t distribution of the difference in the log-transformed values for GM. The means and 95% CIs were back-transformed to the original scale for presentation.

^eSeroresponse relative to baseline at a participant level was defined as a change from below the LLOQ to equal or above 4× LLOQ, or at least a 4-fold rise if baseline was equal to or above the LLOQ. The 95% CIs were calculated using the Clopper-Pearson method.

^fThe SRR difference 95% CIs was calculated using the Miettinen-Nurminen (score) confidence limits.

Safety

A total of 48/49 (98.0%) and 1303/1356 (96.1%) of participants contributed solicited safety data in the placebo-mRNA-1273-booster and mRNA-1273-booster groups, respectively. Most participants (1278/1351; 94.6%) reported ≥ 1 solicited AR within 7 days of the mRNA-1273 booster. Frequently reported (>10% of participants) local ARs were pain, swelling, and axillary swelling or tenderness; frequent systemic ARs were fatigue, headache, myalgia, chills, arthralgia, and nausea/vomiting (Figure 3). Most ARs were grade 1 or 2 in severity, and no grade 4 ARs were reported. The median (range) onset of any AR was 1 (1–7) days after vaccination and median (range) durations were 3 (1–33) days and 2 (1–27) days for local and systemic ARs, respectively. Overall rates of solicited ARs were similar in participants with and without SARS-CoV-2 infection before mRNA-1273 booster (ie, SARS-CoV-2 pre-booster–positive and SARS-CoV-2 pre-booster–negative; data not shown). However, rates of solicited systemic ARs (particularly ARs of fever, headache, fatigue, and chills) were lower among SARS-CoV-2 pre-booster–positive participants (68.9%) compared with SARS-CoV-2 pre-booster–negative participants (80.7%).

Figure 3.

Local (a) and systemic (b) adverse reactions by grade within 7 days after mRNA-1273 booster.

N = 1351. Percentages were based on the number of exposed participants who submitted any data for the event. 95% CIs were calculated using the Clopper-Pearson method.

Up to 28 days after mRNA-1273 booster, 14.9% of participants (209/1405) reported unsolicited TEAEs; 0.3% (4/1405) reported severe TEAEs and 8.5% (119/1405) reported MAAEs (Table S5). TEAEs considered by the investigator to be vaccine-related were reported by 4.2% of participants (59/1405), the most frequent of which were known reactogenicity events (headache, 1.6%; 23/1405; and fatigue, 1.5%; 21/1405). Rates of MAAEs (2/1405 [0.1%]) and severe TEAEs (3/1405 [0.2%]) considered by the investigator to be vaccine-related were low; no SAEs or AESIs were reported. Throughout the booster phase (up to 6 months post-booster), no SAEs or AESIs were assessed by the investigator as vaccine-related. No deaths occurred, and no participants discontinued from the trial due to an AE; further, no cases of MISC-C or events of myocarditis or pericarditis were reported (Table S6). The most commonly reported MAAE was COVID-19 (189/1405 [13.5%]).

Incidence

The surge in omicron variant prevalence in January 2022 provided a unique opportunity to assess the impact of the booster on COVID-19 incidence among those boosted in a short time window (starting December 27, 2021) just prior to the peak of omicron surge; the symptomatic COVID-19 incidence rates in January 2022 were 0 and 95.766 cases per 1000 person-months in the boosted and non-boosted groups, respectively (Table S7). No COVID-19 cases were assessed as severe, and no COVID-19–related hospitalizations or deaths were reported.

Discussion

We previously demonstrated that the 2-dose mRNA-1273 100-µg primary vaccine series was efficacious in adolescents⁷ and induced robust antibody responses at 1 month following the primary series. Although a decline in the nAb levels was observed thereafter, they remained markedly above baseline levels through 6 months after vaccination, with the magnitude of antibody levels at 6 months maintained through 1 year after completing the primary series.¹⁵ The emergence of variants, including delta and BA.1 omicron, with the ability to circumvent vaccine-mediated immunity prompted the evaluation of booster doses to enhance protection against SARS-CoV-2 variant-associated morbidity and mortality. Since then, new highly transmissible omicron SARS-CoV-2 subvariants, most recently omicron KP.3.1.1, have emerged in the United States.¹⁶

Here, we demonstrate inferred effectiveness of an mRNA-1273 booster dose in adolescents aged 12–17 years, which supported the authorization of a booster to enhance protection against COVID-19 in adolescents who received the mRNA-1273 primary series.¹⁷ Immunobridging strategies are widely accepted as an approach to infer vaccine effectiveness in clinical trials once direct vaccine efficacy has been established in clinical endpoint efficacy trials that demonstrate protection against disease.^18,19 Available data support the use of antibody responses, specifically nAb, as a surrogate endpoint.^20–23 In a study evaluating immune correlates of a 3-dose regimen of mRNA-1273 in the adult COVE trial, bAbs and nAbs were shown to be inversely correlated with omicron (BA.1) COVID-19 risk in both SARS-CoV-2–negative and –positive participants.²⁴ Among SARS-CoV-2–negative individuals, 3-dose vs 2-dose booster efficacy correlated with predicted nAb titers at exposure, with estimates of −8% (95% CI: −126% to 48%), 50% (25% to 67%), and 74% (49% to 87%), at 56, 251, and 891 Arbitrary Units/mL, respectively. While these data were collected during a period in which previous variants were circulating,^20,22–24 together, these findings highlight the benefits of boosting to confer continued protection against emerging variants. As new SARS-CoV-2 variants continue to emerge,^25–27 ongoing monitoring of neutralization and vaccine effectiveness of variant-containing mRNA vaccines is essential to guide the development of future COVID-19 vaccination strategies.

In the present study, an mRNA-1273 50-µg booster dose, administered a median of 315 days after the primary series, enhanced pre-booster nAb responses against ancestral SARS-CoV-2 (D614G) by approximately 18-fold among pre-booster SARS-CoV-2–negative adolescents; these responses were noninferior to those observed after the primary series in young adults in the pivotal phase 3 COVE trial, where vaccine efficacy was established.²⁸ Antibody responses against ancestral SARS-CoV-2 (D614G) were also enhanced (approximately 5-fold relative to pre-booster levels) in pre-booster SARS-CoV-2–positive adolescents. As demonstrated in preclinical and longitudinal studies in adults, the primary mRNA vaccine series can elicit virus-specific immune memory cells.^29–31 Repeated dosing from the initial mRNA-1273 vaccination series induces spike protein-specific CD4⁺ T-cell responses that exhibit a T helper 1 (Th1) biased profile (ie, expressing tumor necrosis factor α, interleukin-2, and interferon γ).³² Interleukin-2 contributes to the proliferation and survival of T cells and the generation of memory T cells that undergo secondary expansion when the same antigen is re-encountered.^33–36 Together, our results suggest that the immunologic memory developed after the primary mRNA-1273 series likely contributed to the enhanced antibody response after booster vaccination.

Additionally, we demonstrate that the mRNA-1273 booster dose in adolescents induced measurable cross-reactive bAb responses against SARS-CoV-2 variants, including beta and delta. At the height of early omicron predominance (January 2022), we demonstrate that COVID-19 incidence rates were lower among boosted participants than among participants who only received the mRNA-1273 primary series; importantly, no COVID-19 cases were assessed as severe, and no COVID-19−related deaths or hospitalizations were reported. However, beyond January 2022, the rapid decrease in the size of the non-booster group as well as the rapid decline in cases over time severely limited comparison of COVID-19 incidence between booster and non-booster participants.

While the COVID-19 incidence findings from January 2022 (coinciding with the earlier omicron BA.1 circulation) are encouraging and consistent with previous effectiveness data on a 3-dose regimen of mRNA-1273 against omicron BA.1, the effectiveness of this regimen against infection with subsequent omicron subvariants (BA.2, BA.2.12.1, BA.4, and BA.5) among adults was shown to decline rapidly in the real-world setting.¹⁰ The clinical benefit of omicron-adapted vaccines is demonstrated by recent observational data showing improved protection against hospitalizations for COVID-19 with bivalent omicron-containing mRNA-1273 (encoding for the ancestral and BA.4/BA.5 strains) compared with ≥ 2 doses of the original mRNA-1273 vaccine (relative vaccine effectiveness [rVE], 95% CI, 70.3% [64.0–75.4]), with no evidence of waning in protection at ≥3 months (rVE, 79.6% [43.2–92.7]).³⁷ More recently, the authorized (year 2023–2024) monovalent omicron XBB.1.5-containing vaccine (administered as a fifth dose to adults who previously received the primary series, a third dose of an original mRNA COVID-19 vaccine, and a fourth dose of an omicron BA.4/BA.5 bivalent vaccine) elicited robust and diverse nAb responses against more recent variants, including JN.1,³⁸ thus indicating the potential utility of using variant-matched vaccines for continued protection in pediatric populations.

While cellular immune responses were not evaluated here, data in adults demonstrated that T-cell responses to mRNA booster vaccination are reactive to the omicron variant, suggesting that booster-mediated T-cell responses may aid in reducing omicron-associated disease severity.³⁹ Additionally, a longitudinal analysis of immune responses in adults showed that the receipt of an mRNA-based booster dose after primary series vaccination also stimulates CD4+ and, to a greater extent, CD8+, T-cell production of interferon γ and tumor necrosis factor α.³⁹ Interferon γ plays an important role in the inhibition of viral replication, while tumor necrosis factor α is involved in controlling infection.^40–43 Taken together, these findings underscore the importance of booster vaccination in maintaining the effectiveness of mRNA-1273 during the early period of omicron transmission. In addition, we showed that booster vaccination is beneficial even in individuals who had detectable SARS-CoV-2 antibodies, highlighting the benefits of booster vaccination in populations with high seroprevalence.

Overall, the mRNA-1273 booster was well-tolerated, and the safety profile at a median follow-up of 204 days was consistent with the known safety profile of the mRNA-1273 primary series in adolescents.⁷ No new safety concerns were observed following the mRNA-1273 booster, and the overall reactogenicity was lower for the booster than the primary series; there were also fewer grade ≥ 3 local and systemic ARs after the booster dose (4.6% and 8.2%, respectively) compared with after dose 2 of the mRNA-1273 primary series (8.9% and 13.8%, respectively).⁷ Unsolicited TEAEs were primarily reflective of infection- and reactogenicity-related events that were typically observed in adolescents during the COVID-19 pandemic. Treatment-related unsolicited TEAEs through 28 days after vaccination were less frequent after the booster (4.2%) than after the primary series (12.6%).⁷ There were no reports of MIS-C or myocarditis/pericarditis.

Strengths and limitations

A strength of this study is the assessment of booster response in SARS-CoV-2–positive adolescents who received the mRNA-1273 primary series, permitting broad applicability of the findings to the US adolescent population, where a high prevalence of hybrid immunity (59.6%) was observed between July and September 2022.⁴⁴ However, while the demographic composition of this study underrepresented Black/African American individuals (3.1%), who comprised 13.7% of the US population in 2023,⁴⁵ previous observations from our pivotal study in adults (where racial and ethnic proportions were generally representative of US demographics) demonstrate comparable vaccine efficacy against the ancestral strain across race and ethnicity subgroups.²⁸ The study has several limitations. First, the omicron-specific humoral immune response, as well as cellular immune responses against SARS-CoV-2, were not assessed. The study was also not designed to address the cross-reactivity of antibody response or the cross-protective efficacy against more recent variants. While this study phase did not evaluate the immunogenicity of heterologous boosting, previous adult data demonstrate immunogenicity of heterologous booster vaccination.¹¹ Additionally, the COVID-19 incidence rates after the booster were compared with the primary series as opposed to a direct comparison to placebo, as it was imperative to offer unvaccinated individuals the opportunity to receive the authorized vaccine during the omicron period. Further, the comparison of COVID-19 incidence between boosted and non-boosted groups may be limited by the co-circulation of delta and omicron variants. The study was also not designed to evaluate the impact of the mRNA-1273 booster on the incidence of severe COVID-19–associated outcomes among recipients stratified by SARS-CoV-2 status at baseline. However, no COVID-19–related hospitalizations or deaths were reported as of the data cutoff.

Conclusions

The overall risk-benefit profile of mRNA-1273 remains favorable in adolescents aged 12–17 years. Vaccine effectiveness of the mRNA-1273 50-µg booster dose was demonstrated by the successful immunobridging of immune responses in adolescents to those after primary series vaccination in young adults. In addition, mRNA-1273 50-µg booster dose administration enhanced nAb levels among pre-booster SARS-CoV-2–negative and SARS-CoV-2–positive participants and appeared to provide protection against COVID-19 during the early period of omicron transmission. These findings highlight the importance of booster vaccination in adolescents as new, highly transmissible variants emerge.

Biography

Amparo Figueroa, MD, is currently serving as a Director of Clinical Development in Infectious Diseases at Moderna, Inc. Dr. Figueroa received her medical degree at the De La Salle University and her Master of Public Health degree at the Harvard School of Public Health. Dr. Figueroa has served as Clinical Development Lead in numerous vaccine clinical trials over the years.

Funding Statement

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

Disclosure statement

AF, WX, WD, BG, FP, JM, and RD are employees of Moderna, Inc., and hold stock/stock options in the company. KA has nothing to disclose. GB received vaccine clinical research payments for work completed for Moderna, Inc. AY and KS are consultants and were contracted by Moderna, Inc., for this study.

Author contributions

Drs Amparo Figueroa, Kashif Ali, Weiping Deng, and Rituparna Das contributed to the study concept and design, contributed to data collection, and were involved in data analysis and interpretation.

Drs Karen Slobod and Jacqueline Miller contributed to the study concept and design and were involved in data analysis and interpretation.

Drs Gary Berman and Bethany Girard contributed to data collection.

Anne Yeakey contributed to data collection and was involved in data analysis and interpretation.

Drs Wenqin Xu and Francis Priddy were involved in data analysis and interpretation.

All authors were involved in writing and/or reviewing the manuscript content and approved the final draft. All authors agree to be accountable for all aspects of the work.

Data availability statement

As the trial is ongoing, access to patient-level data presented in the article and supporting clinical documents by qualified external researchers who provide methodologically sound scientific proposals may be available upon reasonable request for products or indications that have been approved by regulators in the relevant markets and subject to review 570 from 24 months after study completion. Such requests can be made to Moderna, Inc., 325 Binney Street, Cambridge, MA 02142; data_sharing@modernatx.com. A materials transfer and/or data access agreement with the sponsor will be required for accessing shared data. All other relevant data are presented in the paper.

Supplementary material

Supplemental data for this article can be accessed on the publisher’s website at https://doi.org/10.1080/21645515.2024.2436714