TY - JOUR
T1 - Comparison of two schedules of two-dose priming with the ten-valent pneumococcal conjugate vaccine in Nepalese children
T2 - an open-label, randomised non-inferiority controlled trial
AU - Kandasamy, Rama
AU - Gurung, Meeru
AU - Thorson, Stephen
AU - Yu, Ly Mee
AU - Galal, Ushma
AU - Voysey, Merryn
AU - Kelly, Sarah
AU - Wahl, Brian
AU - Berbers, Guy
AU - Finnegan, Kier
AU - Ansari, Imran
AU - Paudel, Krishna
AU - Murdoch, David R.
AU - O'Brien, Katherine L.
AU - Kelly, Dominic F.
AU - Goldblatt, David
AU - Shrestha, Shrijana
AU - Pollard, Andrew J.
N1 - Funding Information:
AJP reports grants from Okairos and Pfizer, which finished within the past 36 months outside the submitted work. AJP is Chair of UK Department of Health's Joint Committee on Vaccination and Immunisation, and Chair of the EMA Scientific Advisory Group on vaccine; however, the views expressed herein do not represent necessarily those of the Department of Health or the Joint Committee on Vaccination and Immunisation. AJP is also a member of WHO's Strategic Advisory Group of Experts. DFK receives salary support from the National Institute for Health Research Oxford Biomedical Research Centre. RK received the Robert Austrian Award in Pneumococcal Vaccinology, which was supported by Pfizer, at the 10th International Symposium on Pneumococci and Pneumococcal Diseases 2016. KLO has had grant funding in the preceding 3 years from Pfizer, the Bill & Melinda Gates Foundation and Gavi for pneumococcal vaccine related research. DG reports grants from vaccine manufacturers GlaxoSmithKline, Sanofi Pasteur, and Merck, outside the submitted work.
Publisher Copyright:
© 2019 Elsevier Ltd
PY - 2019/2
Y1 - 2019/2
N2 - Background: Nepalese infants receive ten-valent pneumococcal conjugate vaccine (PCV10) with a 1 month interval between priming doses for programmatic reasons. We aimed to investigate whether immune responses to PCV10 serotypes were non-inferior if the second priming dose of PCV10 was delivered at a 1 month interval as opposed to a 2 month interval. Methods: We did an open-label, randomised, parallel group trial in healthy Nepalese infants aged 40–60 days at Patan Hospital, Kathmandu, Nepal. Children were eligible for inclusion if they were healthy, were born at more than or equal to 37 weeks' gestation, were residing in Kathmandu, and had not had any previous vaccinations other than BCG, and oral polio vaccine. Participants were randomly assigned (1:1) by means of a computer-generated list with randomly varying permuted block sizes accessed through a validated web-based interface, to receive PCV10 either at 6 weeks and 10 weeks of age (6 + 10 group) or at 6 weeks and 14 weeks of age (6 + 14 group), with both groups receiving a booster at 9 months of age. Laboratory staff, masked to study intervention, analysed serum samples for antibodies against PCV10 serotypes by ELISA. The primary outcome was to determine whether the 6 + 10 schedule was non-inferior to the 6 + 14 schedule at 9 months of age, on the basis of the proportion of infants with serotype-specific IgG greater than or equal to 0·35 μg/mL. Non-inferiority was established with a 10% margin, and the primary endpoint was measured in a modified intention-to-treat population, which included only participants who successfully had a blood sample collected. This trial is registered at ClinicalTrials.gov, number NCT02385513. Findings: Between Aug 21, 2015, and April 4, 2016, 304 Nepalese children were randomly assigned to either the 6 + 10 group (n=152) or the 6 + 14 group (n=152). At 9 months of age, the 6 + 10 schedule was non-inferior for serotype 5 (79 [55·2%] of 143 vs 78 [53·4%] of 146, difference 1·82% [95% CI −9·6 to 13·25], p=0·021), serotype 9V (66 [46·1%] of 143 vs 55 [37·6%] of 146, difference 8·48% [−2·84 to 19·8], p=0·001), serotype 14 (110 [77·4%] of 142 vs 110 [74·8%] of 147, difference 2·63% [−7·27 to 12·54], p=0·006), and serotype 19F (135 [95%] of 142 vs 146 [100%] of 146, difference −4·92% [−9·86 to 0], p=0·022). At the same timepoint, non-inferiority was not shown for serotype 1 (36 [25·1%] of 143 vs 42 [28·5%] of 147, difference −3·39% [95% CI −13·56 to 6·77], p=0·102), serotype 4 (70 [48·9%] of 143 vs 87 [59·1%] of 147, difference −10·23% [−21·64 to 1·18], p=0·516), serotype 6B (96 [67·1%] of 143 vs 114 [77·5%] of 147, difference −10·41% [−20·65 to −0·18], p=0·532), serotype 7F (99 [69·2%] of 143 vs 109 [74·1%] of 147, difference −4·91% [−15·26 to 5·42], p=0·168), serotype 18C (89 [62·2%] of 143 vs 114 [77·5%] of 147, difference −15·31% [−25·78 to −4·83], p=0·840), and serotype 23F (37 [25·8%] of 143 vs 41 [27·8%] of 147, difference −2·01% [−12·19 to 8·16], p=0·062). After the booster dose, at 10 months of age, there were no significant differences in immunogenicity (proportion of children with antibody greater than or equal to 0.35 μg/mL) for any of the ten serotypes, when comparing the two schedules. Serious adverse events occurred in 32 participants, 11 (7%) of 152 in the 6 + 10 group and 21 (14%) of 152 in the 6 + 14 group. Interpretation: The 6 week, 14 week, and 9 month schedule should be implemented where possible. However, post-booster responses, which are thought to drive herd immunity, were similar in the two schedules. Therefore, the 6 week, 10 week, and 9 month schedule is an alternative that can be used when logistically necessary, and is expected to provide herd protection. Funding: Gavi, the Vaccine Alliance.
AB - Background: Nepalese infants receive ten-valent pneumococcal conjugate vaccine (PCV10) with a 1 month interval between priming doses for programmatic reasons. We aimed to investigate whether immune responses to PCV10 serotypes were non-inferior if the second priming dose of PCV10 was delivered at a 1 month interval as opposed to a 2 month interval. Methods: We did an open-label, randomised, parallel group trial in healthy Nepalese infants aged 40–60 days at Patan Hospital, Kathmandu, Nepal. Children were eligible for inclusion if they were healthy, were born at more than or equal to 37 weeks' gestation, were residing in Kathmandu, and had not had any previous vaccinations other than BCG, and oral polio vaccine. Participants were randomly assigned (1:1) by means of a computer-generated list with randomly varying permuted block sizes accessed through a validated web-based interface, to receive PCV10 either at 6 weeks and 10 weeks of age (6 + 10 group) or at 6 weeks and 14 weeks of age (6 + 14 group), with both groups receiving a booster at 9 months of age. Laboratory staff, masked to study intervention, analysed serum samples for antibodies against PCV10 serotypes by ELISA. The primary outcome was to determine whether the 6 + 10 schedule was non-inferior to the 6 + 14 schedule at 9 months of age, on the basis of the proportion of infants with serotype-specific IgG greater than or equal to 0·35 μg/mL. Non-inferiority was established with a 10% margin, and the primary endpoint was measured in a modified intention-to-treat population, which included only participants who successfully had a blood sample collected. This trial is registered at ClinicalTrials.gov, number NCT02385513. Findings: Between Aug 21, 2015, and April 4, 2016, 304 Nepalese children were randomly assigned to either the 6 + 10 group (n=152) or the 6 + 14 group (n=152). At 9 months of age, the 6 + 10 schedule was non-inferior for serotype 5 (79 [55·2%] of 143 vs 78 [53·4%] of 146, difference 1·82% [95% CI −9·6 to 13·25], p=0·021), serotype 9V (66 [46·1%] of 143 vs 55 [37·6%] of 146, difference 8·48% [−2·84 to 19·8], p=0·001), serotype 14 (110 [77·4%] of 142 vs 110 [74·8%] of 147, difference 2·63% [−7·27 to 12·54], p=0·006), and serotype 19F (135 [95%] of 142 vs 146 [100%] of 146, difference −4·92% [−9·86 to 0], p=0·022). At the same timepoint, non-inferiority was not shown for serotype 1 (36 [25·1%] of 143 vs 42 [28·5%] of 147, difference −3·39% [95% CI −13·56 to 6·77], p=0·102), serotype 4 (70 [48·9%] of 143 vs 87 [59·1%] of 147, difference −10·23% [−21·64 to 1·18], p=0·516), serotype 6B (96 [67·1%] of 143 vs 114 [77·5%] of 147, difference −10·41% [−20·65 to −0·18], p=0·532), serotype 7F (99 [69·2%] of 143 vs 109 [74·1%] of 147, difference −4·91% [−15·26 to 5·42], p=0·168), serotype 18C (89 [62·2%] of 143 vs 114 [77·5%] of 147, difference −15·31% [−25·78 to −4·83], p=0·840), and serotype 23F (37 [25·8%] of 143 vs 41 [27·8%] of 147, difference −2·01% [−12·19 to 8·16], p=0·062). After the booster dose, at 10 months of age, there were no significant differences in immunogenicity (proportion of children with antibody greater than or equal to 0.35 μg/mL) for any of the ten serotypes, when comparing the two schedules. Serious adverse events occurred in 32 participants, 11 (7%) of 152 in the 6 + 10 group and 21 (14%) of 152 in the 6 + 14 group. Interpretation: The 6 week, 14 week, and 9 month schedule should be implemented where possible. However, post-booster responses, which are thought to drive herd immunity, were similar in the two schedules. Therefore, the 6 week, 10 week, and 9 month schedule is an alternative that can be used when logistically necessary, and is expected to provide herd protection. Funding: Gavi, the Vaccine Alliance.
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U2 - 10.1016/S1473-3099(18)30568-1
DO - 10.1016/S1473-3099(18)30568-1
M3 - Article
C2 - 30635252
AN - SCOPUS:85060712845
SN - 1473-3099
VL - 19
SP - 156
EP - 164
JO - The Lancet Infectious Diseases
JF - The Lancet Infectious Diseases
IS - 2
ER -