Table 1.
Characteristics of studies included in the systematic review and meta-analyses: safety and immunogenicity of vaccines administered to pregnant women living with HIV.
| Authors and country | Study setting/design | Inclusion criteria | Total sample size/(specified number PWLWH) | Type of vaccine given and formulation | Gestational age (GA) at vaccination and number of doses given | Reactogenicity: Solicited adverse events (AEs) | Safety: Maternal and fetal serious unsolicited AEs | Time intervals–sample collection for antibody measurements | Immunogenicity primary outcome and measure | Immunogenicity result summary |
|---|---|---|---|---|---|---|---|---|---|---|
| Almeida, V.D.C. et al., 2009; Brazil | Two referral services hospitals; Prospective Cohort | All pregnant women with HIV infection | 46 (46 PWLWH) | 23-valent pneumococcal polysaccharide vaccine (Pneumo-23) 25 μg of each capsular polysaccharide (serotypes 1, 3, 5, 6 B, 9 V and 14) | GA 32–34 weeks, one dose | Mild local reactions in 6.8% (n = 44) of women (local reactions: pain, edema and erythema) | 4.4% (n = 46) of enrolled infants diagnosed with HIV within a month of birth | Mothers: pre-vaccination, at delivery. Infants: at birth, 1,2,3 and 6 months |
Quantification of IgG antibodies against serotypes (1,3,5,6 B, 9 V and 14) | 1.5–2.9-fold increase in antibody titers. Frequency of ≥2-fold response 22.7–63.6%. Except serotype 3 which did not generate a response. |
| Richardson, K. and Weinberg, A.,2011; USA | Single site; Prospective open-label cohort study | Pregnant women with and without HIV infection | 38 (20 PWLWH, 18 HIV-uninfected) | Trivalent inactivated influenza vaccine (IIV3) antigens varied according to year | GA not specified, one dose given | Not applicable | Not applicable | Baseline, 6 weeks post vaccination, 12 weeks post delivery | Comparison of: Hemagglutination inhibition titers (HAI), Cell-mediated immunity (CMI) assays, flow cytometry |
HAI: significantly lower response in PWLWH for influenza A; equally low for influenza B. CMI: no significant vaccine response in either group Cytometry: significantly greater increase in CD4 subtypes in infected women |
| Abzug, M. et al., 2013; USA | 31 US International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) group sites | Pregnant women with HIV infection | 127 (127 PWLWH) | 30 μg unadjuvanted, inactivated pH1N1 | GA 14–34 weeks, two doses 21 days apart | 3.1% (n = 127) reported local and systemic reactions (local reactions: pain, tenderness, erythema, pruritis; systemic: headache, rhinorrhea, chills) | One fetal death 26 weeks of undetermined etiology. | Mothers: at entry (pre-vaccination), 21 days after dose 1, 10 and 21 days after dose 2 Infants: at delivery, 3 and 6 months |
Complete response (both seroprotection (≥40HAI titer) and seroresponse (≥4-fold increase from baseline)) measured by HAI | Complete response rate was 61% after dose 1 and 65% post dose 2. Seroprotection attained by 66% and 75% post doses 1 and 2 respectively. 59% mothers and 12% infants had seroprotective titers 6 months post delivery |
| Madhi, S.A. et al., 2014; South Africa | Four Antenatal Clinics (ANCs); Double-blind placebo controlled randomized controlled trial (RCT) | Pregnant women with and without HIV infection | 2116 (194 PWLWH) | Trivalent Inactivated Influenza Vaccine (IIV3) VAXIGRIP 15 μg each of A (H1N1), A (H3N2), B(Victoria) or placebo | GA 20–36 weeks | PWLWH analyzable for reactogenicity (n = 97): severe local event in 4.1% and 18.6% severe systemic event. PWWH(n = 181) severe local events-5% and 15% severe systemic | Preterm births-204,8 fetal deaths, 24 stillbirths, 22 infant and 4 maternal deaths | Baseline (pre-vaccination) and 1-month post vaccination | Vaccine-specific seroconversion: Increase in HAI to ≥1:40 if initially ≤1:10, or ≥4-fold increase if initially ≥1:10 | Seroconversion in HIV-uninfected vs HIV-infected treatment arms: A (H1N1) 72.5% vs 42.9%; A (H3N2) 64.8% vs 35.7%; B(Victoria) 92.3% vs 40.0% |
| Nunes, M.C. et al., 2015; South Africa | One ANC; RCT (Sub-study of Madhi et al., 2014) | Pregnant women with HIV and without HIV infection | 198 (98 HIV uninfected and 100 PWLWH) | Trivalent inactivated influenza vaccine (IIV3) VAXIGRIP 15 μg each of A (H1N1), A (H3N2), B(Victoria) | GA not specified, one dose given | Not applicable | Not applicable | Mothers: pre-vaccination, 1-month postvaccination, at delivery, 24 weeks post delivery Infants: within 1 week of birth, 8,16 and 24 weeks of age |
Antibody quantification and persistence; seroconversion (≥1:40HAI and ≥4-fold increase) HAI | Seroconversion at 1 month in HIV-uninfected vs HIV-infected: A (H1N1) 70.0% vs 40.3%; A (H3N2) 63.3% vs 35.7%; B(Victoria) 91.7% vs 40.0%. At 24 weeks, the HIV-uninfected group maintained increased titers to A (H3N2) and B. HIV-infected titers returned to pre-vaccine levels. |
| Weinberg, A. et al., 2015; USA | 31 US IMPAACT sites; Nested-exploratory descriptive study (Sub-study of Abzug et al., 2013) | All pregnant women with HIV infection | 119 PWLWH (57 in sub-study) | Double strength (30 μg) unadjuvanted inactivated pH1N1 vaccine | GA 14–34 weeks, two doses given 21–28 days apart | Not applicable | Not applicable | At entry, pre-vaccination, before dose 2 (anticipated peak primary antibody response); 10–14 days post dose 2: peak anamnestic response | Quantification of HAI, CMI assays, IgG/IgA FluoroSpot, B/T-cell phenotyping | pH1N1 titers significantly increased post dose 1. IgG secreting cells significantly increased post dose 1. IFNy effector T-cells tended to decrease post vaccine. Granzyme B cells had marginal significant increase post dose 1. |
| Heyderman, R. et al., 2016; Malawi/South Africa | Two ANCs; Prospective open-label cohort study | Pregnant women with and without HIV infection, and their infants | 270 women (90 HIV uninfected, 89 PWLWH and CD4 count >350, 91 PWLWH and CD4 count >50 and ≤ 350); 266 infants (87; 88; 91 in respective groups) |
Glycoconjugate GBS vaccine (5 μg each of serotypes Ia, Ib, III) | GA 24–35, one dose given | 1.14% and 4% (n = 175) of PWLWH reported a severe local and systemic reaction respectively compared to 4.4% and 10% (n = 90) of PWWH | 1 maternal death, 1 stillbirth, 7 infant deaths. | Mothers: 15- and 31-days post vaccination and at delivery. Infants: at delivery, day 42. |
Placental transfer of GBS serotype-specific antibodies, and maternal antibodies. IgG concentration measured by specific ELISA protocol. | Antibody concentration higher post-vaccine in all groups. Higher response in HIV-uninfected than HIV-infected women. No difference between high/low CD4 count groups. |
| Nunes, M. C. et al., 2018; South Africa | Four ANCs; Double-blind placebo-controlled RCT. (Sub-study of Madhi et al., 2014) | Pregnant women with and without HIV infection | 155 (75 HIV uninfected and 80 PWLWH) | IIV3 VAXIGRIP 15 μg each of A (H1N1), A (H3N2), B(Victoria) | GA 20–36 weeks | Not applicable | Not applicable | Pre-vaccination, 1-month post vaccination | Comparison of Microneutralization and HAI assays | Microneutralization assay more sensitive, giving fold increases of 2–3 times higher than HAI |
| Dhar N. et al., 2020; South Africa | Placebo controlled RCT. (Stored Samples from Madhi et al., 2014) | Pregnant women with and without HIV infection | 140 PWLWH (77 IIV3 and 68 Placebo), 145 HIV uninfected (68 IIV3 and 77 placebo) | IIV3 VAXIGRIP 15 μg each of A (H1N1), A (H3N2), B(Victoria) or placebo | GA 20–36 weeks | Not applicable | Not applicable | Pre-vaccination, 1-month post vaccination | Comparison of H1/stalk IgG and HAI assays, analysis with regard to infection rate | H1/stalk IgG and HAI higher in PWWH vs PWLWH at all points. H1/stalk increased 2.24-fold vs 1.79-fold after vaccine; HAI increased 5.1–11.3-fold vs 2.3–3.4-fold. |
| Nunes, M.C. et al., 2020; South Africa | Seven ANCs; Double-blind RCT | All Pregnant women with HIV infection | 800 PWLWH | IIV3 containing 15 μg of A/H1N1, A/H3N2, B/Yamagata. Randomized to receive single dose, double dose, or two single doses one month apart (266:265:269 women respectively) | GA 12–36 weeks | PWLWH(n = 772); local reactions greater in double than single dose (47.8% vs 38.1%). Severe systemic reaction greater in single than double dose (10.4% vs 5.5%) after dose 1. Severe local reaction-6% and severe systemic-8.8% | 136 preterm births, 21 fetal deaths, 22 infant and 4 maternal deaths | Pre-vaccination, 1-month post vaccination | Seroconversion rate (≥1/40HAI titers after vaccination with ≥4-fold increase) | Double dose more immunogenic vs single or two single doses. Seroconversion for A/H1N1, A/H3N2, B/Yamagata in double dose group: 65%, 52%, 29%; single dose: 49%, 41%, 18%; two single doses: 52%, 47%, 23%. |
| Weinberg, A. et al., 2021; Brazil | Eight out-patient clinics; Double-blind placebo controlled RCT | All pregnant women with HIV infection | 347 PWLWH | Conjugated and Polysaccharide Pneumococcal vaccines (PCV-10 and PPV-23) or placebo | GA ≥14 and < 34 weeks | Adverse events similar across treatment groups, except injection site and grade 2 systemic reactions more frequent in treatment arms. | Low rate of preterm birth in PCV-10 group (2%, vs 13% and 12% in PPV-23 and placebo). | Mothers: Baseline, 4 weeks post vaccination, at delivery, 24 weeks postpartum. Infants: at birth, 8, 16, 24 weeks |
Mothers: seroresponse, defined as ≥2-fold increase in anti-PNC antibody concentration measured by ELISA against ≥5 of 7 measured serotypes | Seroresponse rates PCV-10 65%; PPV-23 65%; placebo 0%. Seroresponse and differences persisted at delivery and 24 weeks postpartum. |
| Duarte, G. et al., 2022; Brazil | 8 sites; Double-blind placebo-controlled RCT. (Stored samples from Weinberg et al., 2021) | All pregnant women with HIV infection | 346 PWLWH | PCV-10, PPV-23, and placebo; one dose given in pregnancy. Postpartum, placebo receipts received a single dose of either PCV-10 or PPV-23. | GA ≥14 and < 34 weeks | Not applicable | Not applicable | Pre-vaccination, 1 month post vaccination | Anti-pneumococcal antibody concentrations for 8 serotypes; memory B- and T- cell responses against 1 serotype for subset | Antibody concentrations robustly increased across groups, but generally lower antepartum than postpartum, and lower in PCV-10 than PPV-23. No appreciable increase in memory response in any group. |
A total number of 3744 pregnant women were involved in the 12 studies, 1714 of these were PWLWH, as indicated above (Table 1) some of the immunogenicity studies were nested within bigger studies, samples analyzed were from the main studies hence these women are counted once.
CMI = Cell mediated immunity. GA = Gestational age. HAI = Hemagglutination inhibition titers. PWLWH = Pregnant women living with HIV. PCV = Conjugated Pneumococcal Vaccine. PPV = Polysaccharide Pneumococcal Vaccine. IIV3 = Trivalent Inactivated Influenza Vaccine.