Safety and immunogenicity of GBS6 in pregnant women living with and without HIV and their infants in Uganda (PREPARE WP4): a double-blind, randomised, placebo-controlled, phase 2 clinical trial

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BACKGROUND: Immunisation in pregnancy against group B streptococcus could reduce severe disease in early infancy; however, there are few data on the safety and immunogenicity of vaccines given to women living with HIV and their infants. We aimed to evaluate the safety, tolerability, and immunogenicity of the hexavalent capsular polysaccharide conjugate group B streptococcus vaccine (GBS6) in pregnant women living with and without HIV, assess infant outcomes, and quantify the placental transfer of vaccine-induced antibodies to their infants. METHODS: We conducted a double-blind, randomised, placebo-controlled, phase 2 clinical trial evaluating the safety, reactogenicity, and immunogenicity of 20 μg GBS6 compared with placebo in pregnant women living with HIV or without HIV in five antenatal care facilities in Kampala, Uganda. Women aged 18-40 years, between 27 weeks + 0 days and 35 weeks + 6 days, with a low-risk singleton pregnancy were randomly assigned (1:1) to receive placebo (normal saline) or GBS6 vaccine containing serotypes Ia-V, which were given 2 weeks after standard of care tetanus and diphtheria vaccination. We used stratified block randomisation by maternal HIV status, with a block size of eight. The unblinded site pharmacist prepared the investigational product in syringes that were fully masked with opaque labels before being provided to the vaccination nurse, thereby maintaining blinding of both study staff and participants. The primary outcomes were maternal and infant safety following vaccination assessed in all participants 2 weeks post-vaccination, 1 month post-vaccination, at delivery, 6 weeks after delivery, 18 weeks after delivery, 6 months after delivery, and 12 months after delivery. Secondary outcomes included maternal and infant antiserotype-specific group B streptococcus-capsular polysaccharide IgG concentrations and placental transfer of vaccine-induced antibodies at delivery and 18 weeks after delivery, summarised as geometric mean concentrations with 95% CIs, and were assessed in the modified intent-to-treat population. The study was registered at ClinicalTrials.gov (NCT05832502). FINDINGS: Between Oct 25, 2022, and Oct 22, 2024, 300 pregnant women (150 [50%] living with HIV and 150 [50%] without HIV) were randomly assigned to receive either GBS6 or placebo. The mother and infant pair were followed up until 12 months after delivery. Solicited adverse events reported up to 7 days post-vaccination were mostly mild-to-moderate and transient. In total, 86 serious adverse events were recorded: 25 among GBS6-vaccinated women without HIV, 18 among GBS6-vaccinated women living with HIV, 25 among women without HIV receiving placebo, and 18 among women living with HIV receiving placebo. Of 86 serious adverse events, one death (1%) occurred due to suspected poisoning: a woman living with HIV who received a placebo. Of 298 births, there were five (2%) stillbirths: one (1%) among 74 women living with HIV who received the GBS6 vaccine, one (1%) among 74 women without HIV who received placebo, and three (4%) among 76 women living with HIV who received placebo. All serious adverse events, including maternal death, were not related to the study vaccine. There were 55 serious adverse events among the infant participants, all of which were deemed unrelated to the study vaccine. Two (4%) deaths occurred: one early neonatal death (multiple congenital anomalies and birth asphyxia) in the placebo group and one sudden infant death (asphyxia) at age 4 months in the GBS6 group. GBS6 induced maternal antibody concentration to all serotypes, with no statistically significant differences observed between pregnant women living with and without HIV 1 month following vaccination. The geometric mean concentrations for pregnant women living with HIV compared with pregnant women without HIV were Ia 12·02 (6·42-22·50) versus 9·38 (5·06-17·41; p=0·575), Ib 3·71 (2·12-6·48) versus 2·52 (1·35-4·71; p=0·362), II 19·50 (12·93-29·41) versus 17·92 (11·76-27·31; p=0·776), III 4·38 (2·54-7·55) versus 5·64 (3·66-8·70; p=0·469), IV 4·26 (2·78-6·53) versus 4·53 (2·88-7·13; p=0·842), and V 0·49 (0·34-0·70) versus 0·52 (0·31-0·85; p=0·870). There was no evidence of a difference in maternal antibody responses between pregnant women living with HIV and without HIV. GBS6 induced strong early antibody concentrations that declined over time but remained higher than placebo at 1 year after delivery, and HIV-exposed infant showed similar responses to the HIV-unexposed infants. INTERPRETATION: GBS6 elicited anti-capsular polysaccharide conjugate antibodies against group B streptococcus in pregnant women that were transferred to their infants, with no evidence of a difference irrespective of HIV status. No statistically significant difference was seen in pregnant women living with HIV compared with pregnant women not living with HIV or their infants in either safety or immunogenicity, suggesting that this vaccine could be used safely in pregnant women living with HIV. FUNDING: The European & Developing Countries Clinical Trials Partnership.

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