Immunogenicity and safety of a single booster dose of NVX-CoV2373 (TAK-019) in healthy Japanese adults who had previously received a primary series of COVID-19 mRNA vaccine: Primary analysis report of a phase 3 open-label trial

Abstract

Background

We evaluated the immunogenicity and safety of a booster dose of NVX-CoV2373 in Japanese adults who had completed a primary series of COVID-19 mRNA vaccine 6–12 months previously.

Methods

This single-arm, open-label, phase 3 study, conducted at two Japanese centres, enrolled healthy adults ≥ 20 years old. Participants received a booster dose of NVX-CoV2373. The primary immunogenicity endpoint was non-inferiority (lower limit of the 95 % confidence interval [CI] ≥ 0.67) of the geometric mean titre (GMT) ratio of titres of serum neutralizing antibodies (nAbs) against the SARS-CoV-2 ancestral strain 14 days after booster vaccination (day 15) in this study, compared with those 14 days after the second primary NVX-CoV2373 vaccination (day 36) in the TAK-019-1501 study (NCT04712110). Primary safety endpoints included local and systemic solicited adverse events (AEs) up to day 7 and unsolicited AEs up to day 28.

Results

Between 15 April 2022 and 10 May 2022, 155 participants were screened and 150, stratified by age (20–64 years old [n = 135] or ≥ 65 years old [n = 15]), received an NVX-CoV2373 booster dose. The GMT ratio between titres of serum nAbs against the SARS-CoV-2 ancestral strain on day 15 in this study and those on day 36 in the TAK-019-1501 study was 1.18 (95 % CI, 0.95–1.47), meeting the non-inferiority criterion. Following vaccination, the proportion of participants who reported local and systemic solicited AEs up to day 7 was 74.0 % and 48.0 %, respectively. The most common local and systemic solicited AEs were tenderness (102 participants [68.0 %]) and malaise (39 participants [26.0 %]), respectively. Seven participants (4.7 %) reported unsolicited AEs between vaccination and day 28; all were severity grade ≤ 2.

Discussion

A single heterologous NVX-CoV2373 booster induced rapid and robust anti-SARS-CoV-2 immune responses, addressing waning immunity in healthy Japanese adults, and had an acceptable safety profile.

ClinicalTrials.gov identifier: NCT05299359.

1. Introduction

At the time of writing, the coronavirus disease 2019 (COVID-19) pandemic remains a major global health issue with significant human, economic, social and political costs. Individuals aged 65 years and above and those with underlying comorbidities have the highest risk of death or severe illness from COVID-19 [1]. Clinical studies and real-world evidence have shown that two-dose COVID-19 primary vaccination regimens are highly effective in reducing serious disease and death caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection [2], [3], [4], [5]. However, observational data suggest that vaccine protection wanes over time [6], [7]. Thus, booster vaccines are being investigated as potential avenues to bolster protection against SARS-CoV-2 variants.

NVX-CoV2373 (Novavax) is a SARS-CoV-2 vaccine that is administered via a deltoid intramuscular injection and contains 5 µg recombinant nanoparticle spike protein (SARS-CoV-2 rS) and 50 µg Matrix-M adjuvant [8]. A primary series of NVX-CoV2373 vaccine, with doses administered 21 days apart, is well tolerated and associated with robust immune responses in healthy adults [4], [5], [8], [9], [10]. Clinical studies in Australia, the UK and the USA, that investigated an NVX-CoV2373 booster dose in participants who had received a primary series of NVX-CoV2373 or a heterologous COVID-19 vaccine, have demonstrated that a booster dose is also well tolerated, and a strong neutralizing antibody response is induced [11], [12].

To date, no studies have specifically investigated the immunogenicity and safety of a heterologous NVX-CoV2373 booster vaccination in a Japanese population. At the time this study was planned (January 2022), approximately 75 % of the population in Japan had completed a primary vaccination series, mostly with a COMIRNATY (tozinameran) COVID-19 vaccine [13], [14]. COMIRNATY is composed of nucleoside-modified mRNA encoding a mutated form of the full-length spike protein encapsulated in lipid nanoparticles and is administered by intramuscular injection [15]. The aim of this phase 3 study of NVX-CoV2372 (Japanese development code: TAK-019) was to evaluate the immunogenicity and safety of a single booster dose in healthy Japanese adults who had completed a primary series of COMIRNATY vaccine 6–12 months before this study.

2. Methods

2.1. Study design

This was a phase 3, single-arm, open-label trial conducted at two centres in Japan (ClinicalTrials.gov identifier NCT05299359). The study commenced on 15 April 2022 and is ongoing at the time of writing. The study was conducted in accordance with the International Conference on Harmonisation Good Clinical Practice Guidelines and the Declaration of Helsinki ethical principles. In accordance with guidance from the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan, the trial design was developed to assess non-inferiority of the geometric mean titre (GMT) ratio of titres of serum neutralizing antibodies (nAbs) against the SARS-CoV-2 ancestral strain in this study, compared with those observed after the second vaccination of participants in the TAK-019-1501 study (NCT04712110) [10]. To ensure comparability between the two studies, the participant population, sample size, serum nAb assay method and measurement facility were matched. The study protocol and amendments were approved by the Institutional Review Board at each study centre. All participants provided written informed consent before enrolment. Participants from the TAK-019-1501 study had provided written informed consent for the secondary use of clinical data obtained from them.

Approximately 150 participants were planned to be enrolled in the study and stratified by age: 100 participants aged 20–64 years and 50 participants aged at least 65 years. The rationale behind the age groupings was to ensure safety and immunogenicity data were collected on older adults (≥ 65 years of age) who have a high risk of COVID-19 burden. Following screening, eligible participants received a single booster dose of NVX-CoV2373 (0.5 ml containing 5 µg SARS-CoV-2 rS plus 50 µg Matrix-M adjuvant) via a deltoid intramuscular injection. Immunogenicity was assessed on days 1, 8 and 15 (Fig. 1 ). Safety data from day 1 to day 28 were assessed on days 1, 8, 15 and 29, ahead of a 12-month follow-up (full study schedule is shown in Table S1). Participants who received any other approved SARS-CoV-2 or experimental coronavirus vaccine during the trial were terminated from the study.

Fig. 1.

Schematic of the trial design. N/n values indicate the number of planned participants. COVID-19, coronavirus disease 2019.

Here, we report immunogenicity data up to day 15 and safety data up to day 28. The primary immunogenicity and safety analyses were performed after all participants had completed the day 29 visit (clinical cut-off date: 11 June 2022).

2.2. Participants

Participants were healthy Japanese men or women who were at least 20 years old (official age of adulthood in Japan at the time the study was planned) and had completed a primary series of COMIRNATY intramuscular injections 6–12 months before the trial vaccination. Key exclusion criteria were: having received a SARS-CoV-2 vaccination that was either not COMIRNATY or an experimental novel coronavirus vaccine before trial participation; having received a booster vaccination (i.e. third dose) with COMIRNATY intramuscular injection or SPIKEVAX (elasomeran) intramuscular injection before trial participation; close contact with anyone known to have had COVID-19 in the 14 days before the trial vaccination; having a SARS-CoV-2 infection before trial participation; travel outside of Japan in the 30 days before trial participation; having a clinically significant active infection or oral temperature of at least 38 °C in the 3 days before the trial vaccination; and a body mass index of 30 kg/m² or higher.

2.3. Immunogenicity outcomes and assessments

The primary immunogenicity endpoint was the GMT ratio of titres of serum nAbs against the SARS-CoV-2 ancestral strain 14 days after the booster vaccination (day 15) in this study, compared with those observed 14 days after the second vaccination (day 36) of participants in the TAK-019-1501 study (NCT04712110) [10], to assess for non-inferiority.

Secondary immunogenicity endpoints included GMTs, geometric mean fold rises (GMFRs) and seroconversion rates (SCRs; defined as the proportion of participants with rises of at least fourfold from baseline) of anti-SARS-CoV-2 rS serum immunoglobulin Gs (IgGs) and serum nAbs (against the SARS-CoV-2 ancestral strain) on days 1, 8 and 15.

Titres of serum nAbs against the SARS-CoV-2 ancestral strain were determined as previously described using a live virus microneutralization assay with an inhibitory concentration of 50 % (50 % microneutralization titre; MN50) that was developed and validated for Novavax by 360biolabs (Melbourne, Australia) [10].

Serum IgGs against the SARS-CoV-2 rS were analysed as previously described using an enzyme-linked immunosorbent assay (ELISA) specific for the SARS-CoV-2 rS (performed at Novavax Clinical Immune Laboratory [Gaithersburg, MD, USA]) [10]. The total anti-SARS-CoV-2 rS IgG titre in a serum sample was quantitated in ELISA units per ml (EU/ml) by comparison to a reference standard curve.

The lower limit of quantification (LLOQ) for antibody titres was 20 MN50 for serum nAbs against the SARS-CoV-2 ancestral strain and 200 EU/ml for serum IgGs against the SARS-CoV-2 rS. If titre values were below the LLOQ, they were replaced by a value that was half the LLOQ. Values higher than the upper limit of quantification (ULOQ) were recorded as the ULOQ values (10,240 MN50 for serum nAbs and 206,767 EU/ml for serum IgGs).

2.4. Safety outcomes and assessments

The primary safety endpoints were the proportion of participants after the booster vaccination who reported local solicited adverse events (AEs) (pain, tenderness, erythema/redness, induration and swelling) or systemic solicited AEs (fever, fatigue, malaise, myalgia, arthralgia, nausea/vomiting and headache) up to day 7, as well as the proportion of participants who reported unsolicited AEs up to day 28, including any serious AE (SAE), AE of special interest (AESI), medically attended AE (MAAE), AE leading to withdrawal from the trial and treatment-related AEs (definitions of these events are provided in Table S2), and the proportion of participants with SARS-CoV-2 infection up to day 28.

An exploratory endpoint was the number of workdays lost, which were defined as days lost owing to an absence from school or work, or equivalent impact on daily activities due to solicited AEs up to day 7 after the booster vaccination.

AEs were graded by the investigator. Criteria for grade 1 (mild) AEs were awareness of symptoms that are easily tolerated, causing minimal discomfort and not interfering with everyday activities, and symptoms relieved with or without symptomatic treatment; grade 2 (moderate) AEs were sufficient discomfort present to cause interference with normal activity, and only partially relieved with symptomatic treatment; and grade 3 (severe) AEs were extreme distress causing significant impairment of functioning or incapacitation, prevents normal everyday activities, and not relieved with symptomatic treatment. Grade 4 (potentially life-threatening) was only used for grading solicited AEs, which were assessed in accordance with the toxicity grading scale for healthy adult and adolescent volunteers enrolled in preventative vaccine clinical trials with minor modifications [16].

Participants were provided with an electronic diary to record their oral body temperature and the presence and severity of any local and systemic solicited AEs up to day 7 after the booster vaccination. Participants were tested for SARS-CoV-2 infection on day 1 and day 15, and at any time throughout the trial if clinical symptoms of COVID-19 were present.

2.5. Statistical analyses

The full analysis set (FAS) and safety analysis set (SAS) both included all participants who received a dose of the NVX-CoV2373 booster. The per protocol set (PPS) included the FAS participants who had evaluable immunogenicity data and did not have significant protocol deviations that influenced the immunogenicity assessment. To achieve 90 % power with the non-inferiority assessment, 132 participants were required in the PPS. Thus, to account for a 10 % dropout rate, 150 participants were planned to be enrolled.

Immunogenicity analyses were conducted using the PPS. For titres of nAbs against the SARS-CoV-2 ancestral strain, we calculated summary statistics, GMTs and two-sided 95 % confidence intervals (CIs). For the GMT ratio between the booster vaccination group in this study and the two-dose primary vaccination group in the TAK-019-1501 study, a two-way analysis of variance (ANOVA) model was used to calculate point estimates and two-sided 95 % CIs. The two-way ANOVA model included log₁₀-transformed titres of serum nAbs against the SARS-CoV-2 ancestral strain on day 15 as a dependent variable, and age group (20–64 years old or ≥ 65 years old) and study group as independent variables. Each estimate by the model was back-transformed to the original scale. As specified in the PMDA guidance document, serum nAb responses to the NVX-CoV2373 booster vaccination in this study were considered non-inferior to those of the primary series of NVX-CoV2373 if the lower limit of the 95 % CI was at least 0.67 [17]. The sensitivity of the ANOVA model was tested using other candidate covariates (sex and body mass index).

SCRs and 95 % CIs were calculated at each time point. For antibody titres and GMFRs from baseline, we calculated summary statistics, GMTs and the two-sided 95 % CIs of each endpoint at each time point. Antibody titres were also analysed by age group (20–64 years old or ≥ 65 years old) and length of interval between the participants’ second dose of the primary COMIRNATY vaccine and their NVX-CoV2373 booster (168–195, 196–223, 224–251 and ≥ 252 days).

Safety analyses were performed using the SAS. AEs were summarized descriptively and compared with data from the TAK-019-1501 study.

3. Results

3.1. Participant demographics and characteristics

Overall, 155 individuals were screened and 150 received an NVX-CoV2373 booster dose (Fig. 2 ). All 150 participants were included in both the FAS and SAS. Of these, one participant withdrew from the study owing to a busy work schedule and another participant had an invalid day 15 blood sample owing to a deviation from the statistical analysis plan. Therefore, the PPS included 148 participants.

Fig. 2.

Patient flow. The FAS and SAS included all participants who received one dose of the NVX-CoV2373 booster vaccination. The PPS included the FAS participants who had evaluable immunogenicity data and did not have significant protocol deviations that influenced the immunogenicity assessment. FAS, full analysis set; PPS, per protocol set; SAP, statistical analysis plan; SAS, safety analysis set.

Participant demographics and characteristics are shown in Table 1 . The median (range) age of participants was 45.0 (20–78) years. In total, 135 participants (90.0 %) were 20–64 years old and 15 participants (10.0 %) were at least 65 years old. The study included 72 men (48.0 %) and 78 women (52.0 %). The median (range) interval between participants’ second COMIRNATY vaccine dose and their NVX-CoV2373 booster dose was 217.5 (183–357) days.

Table 1.

Participant demographics and baseline characteristics (safety analysis set).

Demographic or characteristic	Safety analysis set (n = 150)
Age, years
Median (range)	45.0 (20–78)
Age group, n (%)
20–64 years	135 (90.0)
≥ 65 years	15 (10.0)
Sex, n (%)
Male	72 (48.0)
Female	78 (52.0)
Body mass index, kg/m2
Mean (SD)	22.7 (2.9)
Race, n (%)
Asian	150 (100)
Other	0
Time since second COMIRNATY vaccine dose, days
Median (range)	217.5 (183–357)

3.2. Immunogenicity analyses

The GMT ratio between titres of serum nAbs against the SARS-CoV-2 ancestral strain 14 days after the booster vaccination (day 15) in this study and those 14 days after the second vaccination (day 36) in the TAK-019-1501 study was 1.18 (95 % CI, 0.95–1.47). When the ANOVA model was adjusted for various candidate covariates in sensitivity analyses, very similar results were obtained. The non-inferiority criterion was met because the lower limit of the 95 % CI was at least 0.67 (Table 2 ).

Table 2.

Non-inferiority analysis as measured by the GMT ratio between titres of serum nAbs against the SARS-CoV-2 ancestral strain at day 15 in this study (TAK-019-3001; per protocol set) and those at day 36 in the TAK-019-1501 study (NCT04712110).

	TAK-019-3001 (n = 148)	TAK-019-1501, (n = 150)
GMT (95 % CI) pre-dose day 1a		10.0 (10.0–10.1)
GMT (95 % CI) pre-dose day 22b		50.2 (41.2–61.0)
GMT (95 % CI) pre-booster dosec	137.1 (112.0–167.7)
GMT (95 % CI)d	1143.9 (1000.5–1307.9)	884.4 (749.0–1044.4)
GMT by LS means of ANOVA	981.7	829.7
GMTRTAK-019-3001/TAK-019-1501 (95 % CI)	1.18 (0.95–1.47)e

ANOVA; analysis of variance; CI, confidence interval; GMT; geometric mean titre; GMTR, geometric mean titre ratio; LS; least squares; nAb, neutralizing antibody; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

^aBefore the first dose of the primary series of NVX-CoV2373.

^bBefore the second dose of the primary series of NVX-CoV2373.

^cBaseline levels of participants in this study.

^dOn day 15 in this study and day 36 in the TAK-019-1501 study.

^ePredefined criterion for non-inferiority: lower limit of 95 % CI of GMTR ≥ 0.67.

For serum IgGs against the SARS-CoV-2 rS (Table 3 ), the GMTs (95 % CI) at baseline and on days 8 and 15 were 5862.3 (4921.0–6983.6), 24,705.9 (21,894.6–27,878.2) and 35,202.2 (31,508.4–39,329.1) EU/ml, respectively. The GMFRs (95 % CI) from baseline to day 8 and from baseline to day 15 were 4.21 (3.69–4.81) and 6.00 (5.17–6.97), respectively. The SCRs (95 % CI) on days 8 and 15 were 53.4 % (45.0–61.6) and 70.9 % (62.9–78.1), respectively.

Table 3.

Immunogenicity responses to the NVX-CoV2373 booster dose by age group (per protocol set).

	Total (n = 148)	Participants 20–64 years old (n = 133)	Participants ≥ 65 years old (n = 15)
Serum IgGs against the SARS-CoV-2 rSa
Baseline
GMT, EU/ml (95 % CI)	5862.3 (4921.0–6983.6)	6070.5 (5110.5–7210.9)	4301.9 (1768.0–10,467.3)
Day 8
GMT, EU/ml (95 % CI)	24,705.9 (21,894.6–27,878.2)	24,899.9 (22,001.3–28,180.5)	23,050.5 (13,662.4–38,889.6)
GMFR from BL (95 % CI)	4.21 (3.69–4.81)	4.10 (3.59–4.69)	5.36 (2.96–9.69)
SCR, n (% [95 % CI])	79 (53.4 [45.0–61.6])	69 (51.9 [43.1–60.6])	10 (66.7 [38.4–88.2])
Day 15
GMT, EU/ml (95 % CI)	35,202.2 (31,508.4–39,329.1)	35,804.2 (31,928.6–40,150.1)	30,289.0 (19,336.2–47,445.9)
GMFR from BL (95 % CI)	6.00 (5.17–6.97)	5.90 (5.06–6.88)	7.04 (3.78–13.10)
SCR, n (% [95 % CI])	105 (70.9 [62.9–78.1])	94 (70.7 [62.2–78.2])	11 (73.3 [44.9–92.2])
Serum nAbs against the SARS-CoV-2 ancestral strainb
Baseline
GMT, MN50 (95 % CI)	137.1 (112.0–167.7)	139.0 (113.6–170.1)	121.3 (45.9–320.2)
Day 8
GMT, MN50 (95 % CI)	729.7 (634.5–839.2)	740.6 (640.2–856.7)	640.0 (371.9–1101.4)
GMFR from BL (95 % CI)	5.32 (4.55–6.23)	5.33 (4.51–6.29)	5.28 (3.08–9.05)
SCR, n (% [95 % CI])	115 (77.7 [70.1–84.1])	103 (77.4 [69.4–84.2])	12 (80.0 [51.9–95.7])
Day 15
GMT, MN50 (95 % CI)	1143.9 (1000.5–1307.9)	1141.3 (994.8–1309.5)	1167.0 (654.8–2080.0)
GMFR from BL (95 % CI)	8.34 (6.93–10.04)	8.21 (6.78–9.94)	9.62 (4.44–20.87)
SCR, n (% [95 % CI])	125 (84.5 [77.6–89.9])	112 (84.2 [76.9–90.0])	13 (86.7 [59.5–98.3])

CI, confidence interval; ELISA, enzyme-linked immunosorbent assay; EU/ml, ELISA units per ml; GMFR, geometric mean fold rise; GMT; geometric mean titre; IgG, immunoglobulin G; LLOQ, lower limit of quantification; MN50, 50 % microneutralization titre; nAb, neutralizing antibody; rS, recombinant nanoparticle spike protein; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SCR, seroconversion rate; ULOQ, upper limit of quantification.

^aAs measured by an ELISA specific for the SARS-CoV-2 rS (LLOQ: 200 EU/ml, ULOQ: 206,767 EU/ml).

^bAs measured by a live virus microneutralization assay with an inhibitory concentration of 50 % (LLOQ: 20 MN50, ULOQ: 10,240 MN50).

Stratified by age (Table 3), the GMTs (95 % CI) of serum IgGs at baseline in participants 20–64 years old and at least 65 years old were 6070.5 (5110.5–7210.9) EU/ml and 4301.9 (1768.0–10,467.3) EU/ml, respectively. The GMTs (95 % CI) of serum IgGs on day 15 in participants 20–64 years old and at least 65 years old were 35,804.2 (31,928.6–40,150.1) EU/ml and 30,289.0 (19,336.2–47,445.9) EU/ml, respectively.

Stratified by length of interval between the participants’ second primary COMIRNATY vaccine dose and their NVX-CoV2373 booster (Table S3), GMTs (95 % CI) of serum IgGs at baseline in participants who had intervals of 168–195, 196–223, 224–251 and at least 252 days were 8892.4 (6387.9–12,378.8), 6284.7 (4718.8–8370.2), 4758.6 (3272.7–6919.0) and 4429.1 (2834.8–6920.0) EU/ml, respectively. The GMTs (95 % CI) of serum IgGs on day 15 in participants who had intervals of 168–195, 196–223, 224–251 and at least 252 days were 32,998.0 (25,672.2–42,414.1), 37,483.3 (31,108.9–45,163.9), 31,952.6 (24,812.7–41,147.1) and 37,794.8 (30,240.8–47,235.9) EU/ml, respectively.

For serum nAbs against the SARS-CoV-2 ancestral strain (Table 3), the GMTs (95 % CI) at baseline and on days 8 and 15 were 137.1 (112.0–167.7), 729.7 (634.5–839.2) and 1143.9 (1000.5–1307.9) MN50, respectively. The GMFRs (95 % CI) from baseline to day 8 and from baseline to day 15 were 5.32 (4.55–6.23) and 8.34 (6.93–10.04), respectively. The SCRs (95 % CI) at days 8 and 15 were 77.7 % (70.1–84.1) and 84.5 % (77.6–89.9), respectively.

Stratified by age (Table 3), the GMTs (95 % CI) of serum nAbs at baseline in participants 20–64 years old and at least 65 years old were 139.0 (113.6–170.1) MN50 and 121.3 (45.9–320.2) MN50, respectively. The GMTs (95 % CI) of serum nAbs on day 15 in participants 20–64 years old and at least 65 years old were 1141.3 (994.8–1309.5) MN50 and 1167.0 (654.8–2080.0) MN50, respectively.

Stratified by length of interval between the participants’ second primary COMIRNATY vaccine dose and their NVX-CoV2373 booster (Table S3), GMTs (95 % CI) of serum nAbs at baseline in participants who had intervals of 168–195, 196–223, 224–251 days and at least 252 days were 177.3 (118.8–264.6), 136.6 (97.9–190.7), 140.8 (88.0–225.4) and 101.7 (64.6–160.2) MN50, respectively. The GMTs (95 % CI) of serum nAbs on day 15 in participants who had intervals of 168–195, 196–223, 224–251 and at least 252 days were 1069.5 (784.6–1457.8), 1161.3 (926.0–1456.4), 1106.2 (815.4–1500.7) and 1246.3 (953.0–1629.9) MN50, respectively.

3.3. Safety analyses

Following vaccination, the proportion of participants who experienced solicited local AEs and solicited systemic AEs up to day 7 was 74.0 % (111/150) and 48.0 % (72/150), respectively (Table S4). Most of these were of severity grade 2 or lower. No grade 4 event was reported. The most frequently reported local solicited AEs were tenderness (102 participants [68.0 %]), pain (80 participants [53.3 %]) and swelling (seven participants [4.7 %]) (Fig. 3 A). The most frequently reported solicited systemic AEs were malaise (39 participants [26.0 %]), headache (37 participants [24.7 %]) and myalgia (29 participants [19.3 %]) (Fig. 3B). The median onset (range) of solicited local and systemic AEs was 1.0 (1–4) day and 2.0 (1–6) days, respectively. The median durations (range) of solicited local and systemic solicited AEs was 3.0 (1–11) days and 2.0 (1–11) days, respectively. The proportion of participants reporting local and systemic solicited AEs up to day 7 was generally lower among those who were at least 65 years old (33.3 % [5/15] and 26.7 % [4/15], respectively) than among those who were 20–64 years old (78.5 % [106/135] and 50.4 % [68/135], respectively) (Fig. 4 and Table S4). The reactogenicity and safety profiles of the NVX-CoV2373 booster dose were consistent with those observed following the primary vaccinations in TAK-019-1501 (Fig. 3 and Fig. 4).

Fig. 3.

The proportion of participants reporting local and systemic solicited AEs in this study (safety analysis set) and the TAK-019-1501 study. Local solicited AEs (A) and systemic solicited AEs (B) reported up to day 7 after the NVX-CoV2373 booster vaccination (3001-B1) and the first (1501-V1) and second (1501-V2) vaccine doses in the TAK-019-1501 study (NCT04712110). AE, adverse event.

Fig. 4.

The proportion of participants, stratified by age, who reported local and systemic solicited AEs in this study (safety analysis set) and the TAK-019-1501 study. Local solicited AEs in participants 20–64 years old (A) and at least 65 years old (B), and systemic solicited AEs in participants 20–64 years old (C) and at least 65 years old (D) reported up to day 7 after the NVX-CoV2373 booster vaccination (3001-B1) and the first (1501-V1) and second (1501-V2) vaccine doses in the TAK-019-1501 study (NCT04712110). AE, adverse event.

In total, seven participants (4.7 %) reported unsolicited AEs (ear pain [n = 1]; abdominal pain and diarrhoea [n = 1]; nasopharyngitis [n = 1]; bacterial skin infection [n = 1]; tooth fracture [n = 1]; cough and oropharyngeal pain [n = 1]; and hypoaesthesia [n = 1]) between vaccination and day 28 (6/135 of those 24–64 years old [4.4 %] and 1/15 of those ≥ 65 years old [6.7 %]) (Table 4 ). Of these, two (1.3 % of all participants) had treatment-related AEs (abdominal pain and diarrhoea [n = 1] and hypoaesthesia [n = 1]) and all had AEs of a severity grade of 2 or lower. There were no deaths or other SAEs and no SARS-CoV-2 infections reported up to day 28. One participant reported an MAAE (tooth fracture) that was considered unrelated to the vaccine.

Table 4.

Unsolicited AEs up to day 28 following the NVX-CoV2373 booster dose (safety analysis set).

Parameter, n (%)	Total (n = 150)	Participants 20–64 years old (n = 135)	Participants ≥ 65 years old (n = 15)
Any AE	7 (4.7)a	6 (4.4)	1 (6.7)
Treatment-related AE	2 (1.3)	1 (0.7)	1 (6.7)
Abdominal pain and diarrhoeab	1 (0.7)	1 (0.7)	0
Hypoaesthesiab	1 (0.7)	0	1 (6.7)
Grade 3	0	0	0
SAE	0	0	0
AESI	0	0	0
MAAE	1 (0.7)c	1 (0.7)	0
TEAE leading to study discontinuation	0	0	0

Severity of AEs was graded by the investigator: grade 1 (mild) = awareness of symptoms that are easily tolerated, causing minimal discomfort and not interfering with everyday activities, relieved with or without symptomatic treatment; grade 2 (moderate) = sufficient discomfort is present to cause interference with normal activity, only partially relieved with symptomatic treatment; grade 3 (severe) = extreme distress, causing significant impairment of functioning or incapacitation, prevents normal everyday activities, not relieved with symptomatic treatment.

AE, adverse event; AESI, adverse event of special interest; MAAE, medically attended adverse event; SAE, serious adverse event; TEAE, treatment-emergent adverse event.

^aNo event occurred in more than one participant.

^bMaximum severity of grade 1 (mild).

^cOne participant reported a tooth fracture that was unrelated to the vaccine.

Of the 149 participants who had assessment records, seven (4.7 %) recorded workdays lost owing to solicited AEs between vaccination and day 7. The median (range) number of workdays that these seven participants lost was 1 day (1–6).

4. Discussion

In this single-arm, open-label, phase 3 study in 150 healthy Japanese adults, a single booster dose of NVX-CoV2373, administered 6–12 months after a primary series of COMIRNATY COVID-19 vaccine, induced rapid and robust immune responses (serum nAbs against the SARS-CoV-2 ancestral strain and serum IgGs against the SARS-CoV-2 rS) within 15 days. The primary endpoint was achieved; non-inferiority was found for the day 15 GMT of serum nAbs against the SARS-CoV-2 ancestral strain compared with the day 36 GMT (14 days after the second dose of the primary NVX-CoV2373 regimen) in the TAK-019-1501 study.

The immune responses on day 15 observed in this study were not inferior to those previously reported in adults on day 15 after the second primary vaccination in the TAK-019-1501 study [9]. In contrast to the slightly weaker immune response of older participants (≥ 65 years old) compared with younger participants (20–64 years old) following the primary series of NVX-CoV2373 in the TAK-019-1501 study, the immune responses of the older participants in this booster study were of a similar magnitude to those of the younger participants. Participants who had longer intervals between their second primary COMIRNATY vaccination and the NVX-CoV2373 booster generally had lower pre-booster antibody titres than those who had shorter intervals between the two vaccines. However, post-booster antibody titres were of a similar magnitude regardless of the interval since the primary vaccination. Thus, immune responses to the NVX-CoV2373 booster dose were generally greater in the groups who had longer intervals between the two vaccines, which suggests that the booster addressed waning immunity after the primary series of COMIRNATY vaccine.

Previous clinical trials have demonstrated that older adults have less pronounced immune responses to primary series of COVID-19 vaccines [10], [18]. This study enrolled fewer participants who were at least 65 years old than originally planned. Thus, age group (20–64 years old or ≥ 65 years old) and study group were included as independent variables in the two-way ANOVA to ensure that the differences in age distributions between the TAK-019-1501 study and this study did not influence the non-inferiority assessment. Because non-inferiority was achieved, it is anticipated that a single heterologous booster dose of NVX-CoV2373, mirroring the expected usage in Japan, will show similar efficacy to a primary series of NVX-CoV2373.

The NVX-CoV2373 booster dose was well tolerated in this study and showed an acceptable safety profile up to day 28. No new safety concerns were identified. The reactogenicity and safety profiles of the NVX-CoV2373 booster dose were consistent with those observed up to day 50 after the first dose, and day 29 after the second dose, of the primary series of NVX-CoV2373 in the TAK-019-1501 study [10]. Furthermore, only seven participants recorded workdays lost between vaccination and day 7, which is consistent with an acceptable safety profile. This is the first study in a Japanese population to include workdays lost owing to AEs after COVID-19 vaccination as an exploratory outcome. Because the number of workdays lost is likely to depend on the study population’s culture and environment, caution is needed in extrapolating these results to other populations. However, these data may be helpful for people deciding which product to select and when they should receive the vaccine.

Limitations of this study include the relatively small sample size and the inclusion of only healthy adults. Although this study endeavoured to include older adults who were more at risk for serious COVID-19 complications, those with co-existing conditions were excluded. Furthermore, although the total sample size was determined based on the statistical power for the primary endpoint, the older age group had a low number of participants. This was owing to enrolment challenges because mRNA booster vaccinations were being received by this age group in Japan at that time. Another limitation of this study was that nAb assay results were only assessed for the SARS-CoV-2 ancestral strain. Therefore, between-strain comparisons of antibody data should be made with caution. Finally, because participants were not randomized across this study and the TAK-019-1501 study, any between-study comparisons may have been biased. Age was identified as a potential confounding factor for the non-inferiority assessment and was therefore planned to be adjusted for. However, there may have been other unmeasured confounders.

5. Conclusion

A single NVX-CoV2373 booster dose induced rapid and robust anti-SARS-CoV-2 immune responses, which addressed waning immunity in healthy Japanese adults after a primary series of COMIRNATY vaccine. The NVX-CoV2373 booster dose was well tolerated and had an acceptable safety profile.

Funding

This study was funded by Takeda Pharmaceutical Company Limited, Tokyo, Japan and the Ministry of Health, Labour and Welfare, Tokyo, Japan.

CRediT authorship contribution statement

Kenji Kuriyama: Conceptualization, Methodology, Investigation, Data curation, Writing – original draft, Writing – review & editing, Visualization, Supervision, Project administration. Kyoko Murakami: Conceptualization, Methodology, Writing – review & editing, Supervision. Taisei Masuda: Conceptualization, Methodology, Writing – review & editing. Kenkichi Sugiura: Formal analysis, Writing – review & editing. Sho Sakui: Formal analysis, Writing – review & editing. Ron P. Schuring: Data curation, Writing – review & editing, Supervision. Mitsuhiro Mori: Conceptualization, Methodology, Resources, Writing – review & editing, Supervision, Project administration, Funding acquisition.

Declaration of Competing Interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Kenji Kuriyama reports a relationship with Takeda Pharmaceutical Company Ltd that includes: employment. Kyoko Murakami reports a relationship with Takeda Pharmaceutical Company Ltd that includes: employment and equity or stocks. Taisei Masuda reports a relationship with Takeda Pharmaceutical Company Ltd that includes: employment. Kenkichi Sugiura reports a relationship with Takeda Pharmaceutical Company Ltd that includes: employment. Sho Sakui reports a relationship with Takeda Pharmaceutical Company Ltd that includes: employment. Ron P. Schuring reports a relationship with Takeda Pharmaceuticals International AG that includes: employment. Mitsuhiro Mori reports a relationship with Takeda Pharmaceutical Company Ltd that includes: employment].

Appendix A. Supplementary material

The following are the Supplementary data to this article:

Data availability

The datasets, including the redacted study protocol, redacted statistical analysis plan, and individual participant data supporting the results of the completed study will be made available after the publication of the final study results within 3 months from initial request to researchers who provide a methodologically sound proposal. The data will be provided after its de-identification, in compliance with applicable privacy laws, data protection, and requirements for consent and anonymization.