Safety, immunogenicity, and transplacental antibody transport of conjugated and polysaccharide pneumococcal vaccines administered to pregnant women with HIV: a multicentre randomised controlled trial

Summary

Background

Pneumococcus remains an important cause of morbidity in pregnant women with HIV and their infants. We compared the safety and immunogenicity of PCV-10 and PPV-23 with placebo administered in pregnancy.

Methods

This double-blind, multicentre, randomised controlled trial was done at eight outpatient clinics in Brazil. Eligible participants were adult women with HIV who were pregnant at a gestational age between 14 weeks and less than 34 weeks and who were taking antiretroviral therapy at study entry. Participants were randomly assigned (1:1:1) to receive either PCV-10, PPV-23, or placebo. Participants and study teams were unaware of treatment allocation. Antibodies against seven vaccine serotypes in PCV-10 and PPV-23 were measured by ELISA. The primary outcomes were maternal and infant safety assessed by the frequency of adverse events of grade 3 or higher; maternal seroresponse (defined as ≥2-fold increase in antibodies from baseline to 28 days after immunisation) against five or more serotypes; and infant seroprotection (defined as anti-pneumococcus antibody concentration of ≥0·35 μg/mL) against five or more serotypes at 8 weeks of life. The study was powered to detect differences of 20% or higher in the primary immunological outcomes between treatment groups. This trial is registered with ClinicalTrials.gov, NCT02717494.

Findings

Between April 1, 2016, and Nov 30, 2017, we enrolled 347 pregnant women with HIV, of whom 116 were randomly assigned to the PCV-10 group, 115 to the PPV-23 group, and 116 to the placebo group. One participant in the PCV-10 group did not receive the vaccine and was excluded from subsequent analyses. The frequency of adverse events of grade 3 or higher during the first 4 weeks was similar in the vaccine and placebo groups (3% [90% CI 1–7] for the PCV-10 group, 2% [0–5] for the PPV-23 group, and 3% [1–8] for the placebo group). However, injection site and systemic grade 2 adverse reactions were reported more frequently during the first 4 weeks in the vaccine groups than in the placebo group (14% [9–20] for the PCV-10 group, 7% [4–12] for the PPV-23 group, and 3% [1–7] for the placebo group). The frequency of grade 3 or higher adverse effects was similar across maternal treatment groups (20% [14–27] for the PCV-10 group, 21% [14–28] for the PPV-23 group, and 20% [14–27] for the placebo group). Seroresponses against five or more serotypes were present in 74 (65%) of 114 women in the PCV-10 group, 72 (65%) of 110 women in the PPV-23 group, and none of the 113 women in the placebo group at 4 weeks post vaccination (p<0·0001 for PPV-23 group vs placebo and PCV-10 group vs placebo). Seroresponse differences of 20% or higher in vaccine compared with placebo recipients persisted up to 24 weeks post partum. At birth, 76 (67%) of 113 infants in the PCV-10 group, 62 (57%) of 109 infants in the PPV-23 group, and 19 (17%) of 115 infants in the placebo group had seroprotection against five or more serotypes (p<0·0001 for PPV-23 vs placebo and PCV-10 vs placebo). At 8 weeks, the outcome was met by 20 (19%) of 108 infants in the PCV-10 group, 24 (23%) of 104 infants in the PPV-23 group, and one (1%) of 109 infants in the placebo group (p<0·0001). Although a difference of 20% or higher compared with placebo was observed only in the infants who received PPV-23 at 8 weeks of life, the difference between the two vaccine groups was not appreciable.

Interpretation

PCV-10 and PPV-23 were equally safe and immunogenic in pregnant women with HIV and conferred similar levels of seroprotection to their infants. In areas in which childhood PCV administration decreased the circulation of PCV serotypes, PPV-23 administration to pregnant women with HIV might be more advantageous than PCV by virtue of including a broader range of serotypes.

Funding

Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Translation

For the Portuguese translation of the abstract see Supplementary Materials section.

Introduction

Pneumococcus has been a leading cause of bacterial pneumonia in pregnant and non-pregnant adults with HIV.¹ Even with the widespread use of antiretroviral therapy (ART), the incidence of invasive pneumococcal disease and pneumonia remains higher in people with HIV than in same-age adults without HIV.² Invasive pneumococcal disease and pneumococcal pneumonia are vaccine-preventable conditions to a large extent.³ There are currently two types of vaccines available against pneumococcus: a polysaccharide vaccine (PPV) that is 23-valent (PPV-23) and two conjugated vaccines (PCVs) that are 10-valent (PCV-10) and 13-valent (PCV-13). The efficacy of PPV-23 in preventing invasive pneumococcal disease and all-cause pneumonia in people with HIV was shown in several non-randomised studies,⁴ but the only prospective, randomised, placebo-controlled trial showed a decrease in all-cause mortality but not in all-cause pneumonia.⁵ The efficacy of PCVs was shown both in children and adults with HIV.6, 7 PCV-7 and PCV-9 were shown to be safe and immunogenic in people with HIV.⁸ However, individuals with lower CD4 cell count or higher concentration of HIV plasma RNA had higher antibody responses to PCV-7 than to PPV-23.⁸ Pregnancy is associated with immunosuppression, which helps to protect the fetus against allogeneic rejection. However, before this study, there was one report on the immunogenicity of PPV-23 in pregnant women with HIV and no data for PCV-10 and PCV-23.⁹

Although the administration of pneumococcal vaccines to adults with HIV has been recommended in the USA for over 25 years, a survey of the International Maternal, Pediatric and Adolescent AIDS Clinical Trials clinical sites done before the inception of this study showed that pneumococcal vaccination was generally not given during pregnancy.³ Around 25% of women in the USA are first diagnosed with HIV during pregnancy.¹⁰ This finding constitutes a missed opportunity, because bacterial pneumonias are more common in pregnant women than in non-pregnant adults with HIV and are associated with an increased risk of maternal morbidity and mortality and adverse pregnancy outcomes.¹ The most common barrier against any vaccine administration during pregnancy is the potential risk of adverse pregnancy outcome perceived by mothers and their health-care providers.¹¹

In addition to maternal protection against infection, vaccination of pregnant women results in transplacental transport of maternal antibodies that might protect infants in the first few months of life. This protection has been clearly shown for influenza and pertussis and has been proposed for other infections, including pneumococcus.12, 13 Although the introduction of PCVs in the childhood schedule of immunisation has generally decreased the incidence of severe pneumococcal disease in children younger than 2 years, infants exposed in utero to HIV still have an increased risk of severe pneumonia and invasive pneumococcal disease irrespective of their HIV infection status.¹⁴ Transplacental transport of pathogen-specific maternal antibodies decreases in the context of HIV infection, and this decrease might contribute to the high risk of invasive pneumococcal disease and severe pneumonia in HIV-exposed infants.¹⁵ This high risk could potentially be mitigated by increasing maternal anti-pneumococcus antibody concentrations through immunisation.

To address the knowledge gap surrounding anti-pneumococcus immunisation in pregnant women with HIV, we designed a randomised, double-blind, placebo-controlled trial to measure the safety, immunogenicity, and transplacental transport of maternal antibodies in women with HIV who have been vaccinated against pneumococcus during pregnancy. The underlying hypotheses were that PPV-23 and PCV-10 were safe and increased maternal pneumococcal antibodies compared with placebo.