Infectivity and Immunogenicity of Live-Attenuated Respiratory Syncytial Virus Vaccines in Human Immunodeficiency Virus-Exposed Uninfected Children

Abstract

Background: Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory illness among young children. Human immunodeficiency virus (HIV)-exposed, uninfected (HEU) children experience a higher burden of RSV disease and have immune abnormalities that may influence their responses to live-attenuated RSV vaccines.

Methods: In a pooled analysis of clinical trials of 7 live-attenuated, intranasal RSV vaccines conducted by the IMPAACT Network among children 6 to <25 months of age with serum RSV-neutralizing titers of <1:40, the infectivity and immunogenicity of these vaccines were compared among HEU and HIV-unexposed, uninfected (HUU) children. Nasal washes were collected during the first 28 days after vaccination. Serum RSV-neutralizing and anti-RSV F glycoprotein immunoglobulin G (IgG) antibodies were measured prior to and 56 days after vaccination, and before and after the following winter season.

Results: Of 156 children, 90 (58%) were HUU and 66 (42%) were HEU. Seventy-six (84%) HUU and 63 (95%) HEU participants were infected with vaccine (shed vaccine virus and/or had a ≥4-fold rise in serum RSV antibodies at 56 days after vaccination). HUU children had higher serum RSV-neutralizing and anti-RSV F IgG titers prior to vaccination. Compared to HEU children, lower percentages of HUU children had ≥4-fold rises in RSV-neutralizing (67% vs 88%) and anti-RSV F IgG (70% vs 89%) titers at 56 days after vaccination.

Conclusions: Live-attenuated RSV vaccines are highly immunogenic in HEU children. Given their increased burden of RSV disease and higher early childhood mortality in some settings, HEU children should be prioritized for vaccination against RSV as these vaccines become available.

Keywords: antibody interference; live-attenuated RSV vaccine; maternal HIV infection; transplacental antibody transfer; vaccine-elicited immunogenicity.

Figure 1.

Kinetics of vaccine virus shedding in nasal wash specimens, by human immunodeficiency virus (HIV) exposure status. Dot plots depict vaccine virus titers in nasal washes collected from HIV-unexposed, uninfected (HUU) and HIV-exposed, uninfected (HEU) study participants during the 28 days after intranasal vaccination. Each point represents a vaccine virus titer measurement by immunoplaque assay (culture, A) or quantitative polymerase chain reaction (qPCR, B) from a single participant for nasal wash samples collected at indicated timepoints (with windows of ± 1 day). Lines depict the median virus shedding at each timepoint, including samples in which shedding was not identified, and are shown by HIV exposure status. Negative cultures and qPCR measurements were assigned values equal to the lower limits of detection for these assays (0.5 log₁₀ plaque-forming units [PFU]/mL and 1.7 log₁₀ copies/mL, respectively). Horizontal jittering was applied to data points to show the large number of participants with values below the limit of detection. Only 2 studies (P1114 and IMPAACT 2000) measured viral shedding on days 19 and 21.

Figure 2.

Serum respiratory syncytial virus (RSV) antibodies before and after vaccination, by human immunodeficiency virus (HIV) exposure status. Box and whisker plots depict antibody titers by RSV 60% plaque reduction neutralization assay (A) and anti-RSV F immunoglobulin G enzyme-linked immunosorbent assay (B), prior to (“Pre”) and 56 days after vaccination (“Day 56”) by HIV exposure status and study. Vaccine candidates (abbreviated) and IMPAACT study numbers (in brackets) are indicated above each plot. Antibody titers are shown on the reciprocal log₂ scale. Values below the lower limits of detection for these assays are indicated by dashed lines. Median values prior to and after vaccination are joined by lines. Abbreviations: HEU, human immunodeficiency virus–exposed, uninfected; HUU, human immunodeficiency virus–unexposed, uninfected; IgG, immunoglobulin G; RSV-PRNT₆₀, serum respiratory syncytial virus 60% plaque reduction neutralizing titers.

Figure 3.

Distribution of changes in serum respiratory syncytial virus (RSV) antibodies during the surveillance period. Changes were calculated as the antibody titer after the RSV surveillance period minus the antibody titer prior to the surveillance period analyzed on the reciprocal log₂ scale. Each bar represents the percentage of all children who experienced a given change in serum antibody titers during the RSV surveillance period as measured by RSV 60% plaque reduction neutralization assay (A) or anti-RSV F immunoglobulin G enzyme-linked immunosorbent assay (B). Density lines are shown by human immunodeficiency virus exposure status and whether RSV was detected in a nasal wash specimen. Abbreviations: anti-RSV F IgG, serum immunoglobulin G antibodies to the RSV F glycoprotein, as determined by enzyme-linked immunosorbent assay; HEU, human immunodeficiency virus–exposed, uninfected; HUU, human immunodeficiency virus–unexposed, uninfected; RSV, respiratory syncytial virus; RSV-PRNT₆₀, serum respiratory syncytial virus 60% plaque reduction neutralizing titers.