TY - JOUR
T1 - Reactogenicity, immunogenicity and breakthrough infections following heterologous or fractional second dose COVID-19 vaccination in adolescents (Com-COV3)
T2 - A randomised controlled trial
AU - the Com-COV3 Study Group
AU - Kelly, Eimear
AU - Greenland, Melanie
AU - de Whalley, Philip C.S.
AU - Aley, Parvinder K.
AU - Plested, Emma L.
AU - Singh, Nisha
AU - Koleva, Stanislava
AU - Tonner, Sharon
AU - Macaulay, Grace C.
AU - Read, Robert C.
AU - Ramsay, Mary
AU - Cameron, J. Claire
AU - Turner, David P.J.
AU - Heath, Paul T.
AU - Bernatoniene, Jolanta
AU - Connor, Philip
AU - Cathie, Katrina
AU - Faust, Saul N.
AU - Banerjee, Indraneel
AU - Cantrell, Liberty
AU - Mujadidi, Yama F.
AU - Belhadef, Hanane Trari
AU - Clutterbuck, Elizabeth A.
AU - Anslow, Rachel
AU - Valliji, Zara
AU - James, Tim
AU - Hallis, Bassam
AU - Otter, Ashley David
AU - Lambe, Teresa
AU - Nguyen-Van-Tam, Jonathan S.
AU - Minassian, Angela M.
AU - Liu, Xinxue
AU - Snape, Matthew D.
N1 - Publisher Copyright:
© 2023 The Authors
PY - 2023/9
Y1 - 2023/9
N2 - Background: This was the first study to investigate the reactogenicity and immunogenicity of heterologous or fractional second dose COVID-19 vaccine regimens in adolescents. Methods: A phase II, single-blind, multi-centre, randomised-controlled trial recruited across seven UK sites from September to November 2021, with follow-up visits to August 2022. Healthy 12-to-16 years olds were randomised (1:1:1) to either 30 µg BNT162b2 (BNT-30), 10 µg BNT162b2 (BNT-10), or NVX-CoV2373 (NVX), 8 weeks after a first 30 µg dose of BNT162b2. The primary outcome was solicited systemic reactions in the week following vaccination. Secondary outcomes included immunogenicity and safety. ‘Breakthrough infection’ analyses were exploratory. Findings: 148 participants were recruited (median age 14 years old, 62% female, 26% anti-nucleocapsid IgG seropositive pre-second dose); 132 participants received a second dose. Reactions were mostly mild-to-moderate, with lower rates in BNT-10 recipients. No vaccine-related serious adverse events occurred. Compared to BNT-30, at 28 days post-second dose anti-spike antibody responses were similar for NVX (adjusted geometric mean ratio [aGMR]) 1.09 95% confidence interval (CI): 0.84, 1.42] and lower for BNT-10 (aGMR 0.78 [95% CI: 0.61, 0.99]). For Omicron BA.1 and BA.2, the neutralising antibody titres for BNT-30 at day 28 were similar for BNT-10 (aGMR 1.0 [95% CI: 0.65, 1.54] and 1.02 [95% CI: 0.71, 1.48], respectively), but higher for NVX (aGMR 1.7 [95% CI: 1.07, 2.69] and 1.43 [95% CI: 0.96, 2.12], respectively). Compared to BNT-30, cellular immune responses were greatest for NVX (aGMR 1.73 [95% CI: 0.94, 3.18]), and lowest for BNT-10 (aGMR 0.65 [95% CI: 0.37, 1.15]) at 14 days post-second dose. Cellular responses were similar across the study arms by day 236 post-second dose. Amongst SARS-CoV-2 infection naïve participants, NVX participants had an 89% reduction in risk of self-reported ‘breakthrough infection’ compared to BNT-30 (adjusted hazard ratio [aHR] 0.11 [95% CI: 0.01, 0.86]) up until day 132 after second dose. BNT-10 recipients were more likely to have a ‘breakthrough infection’ compared to BNT-30 (aHR 2.14 [95% CI: 1.02, 4.51]) up to day 132 and day 236 post-second dose. Antibody responses at 132 and 236 days after second dose were similar for all vaccine schedules. Interpretation: Heterologous and fractional dose COVID-19 vaccine schedules in adolescents are safe, well-tolerated and immunogenic. The enhanced performance of the heterologous schedule using NVX-CoV2373 against the Omicron SARS-CoV-2 variant suggests this mRNA prime and protein-subunit boost schedule may provide a greater breadth of protection than the licensed homologous schedule. Funding: National Institute for Health Research and Vaccine Task Force. Trial Registration: International Standard Randomised Controlled Trial Number registry: 12348322.
AB - Background: This was the first study to investigate the reactogenicity and immunogenicity of heterologous or fractional second dose COVID-19 vaccine regimens in adolescents. Methods: A phase II, single-blind, multi-centre, randomised-controlled trial recruited across seven UK sites from September to November 2021, with follow-up visits to August 2022. Healthy 12-to-16 years olds were randomised (1:1:1) to either 30 µg BNT162b2 (BNT-30), 10 µg BNT162b2 (BNT-10), or NVX-CoV2373 (NVX), 8 weeks after a first 30 µg dose of BNT162b2. The primary outcome was solicited systemic reactions in the week following vaccination. Secondary outcomes included immunogenicity and safety. ‘Breakthrough infection’ analyses were exploratory. Findings: 148 participants were recruited (median age 14 years old, 62% female, 26% anti-nucleocapsid IgG seropositive pre-second dose); 132 participants received a second dose. Reactions were mostly mild-to-moderate, with lower rates in BNT-10 recipients. No vaccine-related serious adverse events occurred. Compared to BNT-30, at 28 days post-second dose anti-spike antibody responses were similar for NVX (adjusted geometric mean ratio [aGMR]) 1.09 95% confidence interval (CI): 0.84, 1.42] and lower for BNT-10 (aGMR 0.78 [95% CI: 0.61, 0.99]). For Omicron BA.1 and BA.2, the neutralising antibody titres for BNT-30 at day 28 were similar for BNT-10 (aGMR 1.0 [95% CI: 0.65, 1.54] and 1.02 [95% CI: 0.71, 1.48], respectively), but higher for NVX (aGMR 1.7 [95% CI: 1.07, 2.69] and 1.43 [95% CI: 0.96, 2.12], respectively). Compared to BNT-30, cellular immune responses were greatest for NVX (aGMR 1.73 [95% CI: 0.94, 3.18]), and lowest for BNT-10 (aGMR 0.65 [95% CI: 0.37, 1.15]) at 14 days post-second dose. Cellular responses were similar across the study arms by day 236 post-second dose. Amongst SARS-CoV-2 infection naïve participants, NVX participants had an 89% reduction in risk of self-reported ‘breakthrough infection’ compared to BNT-30 (adjusted hazard ratio [aHR] 0.11 [95% CI: 0.01, 0.86]) up until day 132 after second dose. BNT-10 recipients were more likely to have a ‘breakthrough infection’ compared to BNT-30 (aHR 2.14 [95% CI: 1.02, 4.51]) up to day 132 and day 236 post-second dose. Antibody responses at 132 and 236 days after second dose were similar for all vaccine schedules. Interpretation: Heterologous and fractional dose COVID-19 vaccine schedules in adolescents are safe, well-tolerated and immunogenic. The enhanced performance of the heterologous schedule using NVX-CoV2373 against the Omicron SARS-CoV-2 variant suggests this mRNA prime and protein-subunit boost schedule may provide a greater breadth of protection than the licensed homologous schedule. Funding: National Institute for Health Research and Vaccine Task Force. Trial Registration: International Standard Randomised Controlled Trial Number registry: 12348322.
KW - Adolescents
KW - BNT162b2
KW - Breakthrough infection
KW - COVID-19
KW - Heterologous
KW - Immunisation
KW - Immunity
KW - NVXCoV2373
KW - SARS-CoV-2
KW - Vaccination
UR - http://www.scopus.com/inward/record.url?scp=85166981952&partnerID=8YFLogxK
U2 - 10.1016/j.jinf.2023.06.007
DO - 10.1016/j.jinf.2023.06.007
M3 - Article
C2 - 37331429
AN - SCOPUS:85166981952
SN - 0163-4453
VL - 87
SP - 230
EP - 241
JO - Journal of Infection
JF - Journal of Infection
IS - 3
ER -