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

Abstract

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory illness (ALRI) among infants and young children. Globally, it is estimated that RSV caused 33 million ALRI episodes, 3.6 million hospital admissions, and >100 000 deaths among children <5 years of age in 2019 [1]. Fortunately, RSV vaccine development has accelerated over the past decade, with several vaccine candidates currently being evaluated for use in children [2]. A bivalent RSV prefusion F protein–based vaccine for pregnant women and an extended half-life monoclonal antibody for infants were recently approved by the United States Food and Drug Administration for the passive protection against RSV disease among infants <6 months of age [3, 4]. However, there remains an urgent need for a pediatric vaccine that effectively induces active immunity to RSV and prevents RSV disease among infants and children >6 months of age, who account for approximately 50% of RSV-associated child deaths globally [5].

Approximately 1.2 million infants are born to women with human immunodeficiency virus (HIV) each year, and >1 million of these infants do not acquire HIV [6]. Despite the absence of HIV infection, these HIV-exposed, uninfected (HEU) children have higher early childhood morbidity and mortality from infections, including ALRI caused by RSV (RSV-ALRI) [7–10]. In a study conducted in South Africa, HEU infants had a 40% higher incidence and more than twice the odds of death from RSV-ALRI during the first 6 months of life than HIV-unexposed, uninfected (HUU) infants [10]. Although multiple factors are likely to contribute to their higher burden of infections, HEU children have a broad range of immune abnormalities postulated to be related to in utero exposure to HIV or antiretroviral medications [11]. In particular, compared to HUU children, HEU children have differences in lymphocyte subsets, have lower neutrophil counts and altered T-lymphocyte function, and acquire lower titers of maternal antibodies specific to several common pathogens [12–17]. These differences in cellular and humoral immunity among HUU and HEU children could have important implications for the effectiveness of vaccines currently in development for the prevention of RSV disease during early childhood.

In this study, pooled analyses of data from phase 1 clinical trials that evaluated 7 live-attenuated intranasal RSV vaccines in children with serum RSV-neutralizing titers of <1:40 were performed. These pooled data were used to compare the infectivity and immunogenicity of these vaccines among HUU and HEU children.

METHODS

Study Design and Analysis Population

This was a retrospective analysis of data from 6 double-blind, randomized, placebo-controlled clinical trials that evaluated the safety, infectivity, and immunogenicity of 7 recombinant live-attenuated RSV vaccines (Supplementary Table 1) [18–23]. Studies were conducted at International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network sites in the United States (Supplementary Table 2) and the Johns Hopkins Center for Immunization Research (Baltimore, Maryland) between October 2013 and September 2020. Although no efforts were made to specifically recruit HEU children into these clinical trials, a high proportion of enrolled children were HEU because of the study populations of other trials being conducted by these IMPAACT Network sites. Eligible participants were 6 to <25 months of age, healthy, without lung disease, and had RSV 60% plaque neutralizing serum antibody titers of <1:40 at screening. In each study, participants were randomly assigned 2:1 to receive a single dose of RSV vaccine or placebo intranasally (day 0). For each of these trials, recruitment occurred outside the time period during which RSV typically circulates (between 1 April and 14 October for most sites), and study participants were followed through the subsequent winter season (RSV surveillance period; between 1 November and 31 March for most sites). Nasal washes were collected on days 3, 5, 7, 10, 12, 14, 17, and 28 (±1 day) relative to vaccination to assess vaccine infectivity, including the magnitude and duration of vaccine virus shedding; in 2 studies (P1114 and IMPAACT 2000), nasal washes were also collected on days 19 and 21. RSV serum antibody titers were measured prior to vaccination, 56 days after vaccination, and before and after the RSV surveillance period. During the RSV surveillance period, a study visit involving a clinical assessment and nasal wash (“illness visit”) was performed for infants who developed medically attended acute respiratory illness, identified based on the presence of fever, symptoms of upper or lower respiratory tract infection, or a diagnosis of acute otitis media. The population analyzed included HUU and HEU children who were randomized to and received an intranasal RSV vaccine. Participants who were randomized to placebo, randomized to vaccine but did not receive the study product, or who had no study visit after vaccine receipt were excluded. No participants were enrolled in >1 study.

Patient Consent Statement

Written informed consent was obtained from a legal guardian for all study participants. These studies were approved by each site's institutional review board, conducted in accordance with the principles of the Declaration of Helsinki and Standards of Good Clinical Practice as defined by the International Conference on Harmonisation, and monitored by the independent data safety and monitoring board of the Division of Clinical Research at the National Institute of Allergy and Infectious Diseases.

Laboratory Methods

To evaluate kinetics of vaccine virus shedding, nasal washes collected during the first 28 days after vaccination were evaluated by immunoplaque assay on Vero cells and by a reverse-transcription quantitative polymerase chain reaction (qPCR) assay specific to the RSV matrix gene, as previously described [24]. Negative cultures and qPCR measurements were assigned values equal to the lower limits of detection (LLD) for these assays (0.5 log₁₀ plaque-forming units [PFU]/mL and 1.7 log₁₀ copies/mL, respectively). Nasal washes collected prior to vaccination and at illness visits conducted during the RSV surveillance period were tested for RSV by qPCR to identify wild-type RSV infections; these samples were also tested for common adventitious agents by multiplex reverse-transcription qPCR (Respiratory Pathogens 21 Assay, Fast-Track Diagnostics, Esch-sur-Alzette, Luxembourg). Serum RSV-neutralizing antibodies (RSV-PRNT₆₀) were measured using a complement-enhanced 60% plaque reduction neutralization assay [25]. Serum immunoglobulin G antibodies to the RSV F glycoprotein (anti-RSV F IgG) were measured using an enzyme-linked immunosorbent assay (ELISA) based on the RSV F glycoprotein derived from strain A2, as previously described [24]. The LLD was 1:10 for the RSV-PRNT₆₀ assay and 1:50 for the anti-RSV F IgG ELISA. Antibody titers were analyzed on the reciprocal log₂ scale. For numerical summaries, measurements below the LLD for the RSV-PRNT₆₀ and anti-RSV F IgG assays were assigned reciprocal log₂ titers equal to half the LLD (2.3 and 4.6, respectively).

Statistical Methods

Participants were considered infected with vaccine if they had a vaccine virus identified by culture or qPCR in a nasal wash up to 28 days after vaccine receipt and/or a ≥4-fold increase in serum RSV-PRNT₆₀ and/or anti-RSV F IgG antibodies between prior to and 56 days after vaccination. The kinetics of viral shedding and proportions of participants infected by study vaccine were summarized by vaccine and HIV exposure status. To account for serum antibody titers below the LLD, a linear regression model for censored data was fit to compare antibody titers by HIV exposure status prior to and 56 days after vaccination [26]. All models were adjusted for age, sex, and the RSV vaccine received; models of antibody titers from 56 days after vaccination were also adjusted for the antibody titer prior to vaccination. Exposure to wild-type RSV during the RSV surveillance period was evaluated through the identification of symptomatic (RSV detected by culture or qPCR in a nasal wash performed as part of an illness visit) or asymptomatic (≥4-fold increase in serum antibody titers as measured by RSV-PRNT₆₀ or anti-RSV F IgG ELISA between prior to and after the RSV surveillance period) infection. A significance level of 5% was used to highlight results, with no adjustments made for multiple testing. Analyses were conducted in SAS version 9.4 software.

RESULTS

Participant Characteristics

Of the 160 children randomized to receive an RSV vaccine across the 6 trials, 4 were excluded from these analyses, including 2 children who did not receive a vaccine and 2 children who received a vaccine but did not have subsequent study visits. Among the 156 children comprising the analysis population, 90 (58%) were HUU and 66 (42%) were HEU. Baseline characteristics of the analysis population are shown in Table 1 (overall) and Supplementary Table 3 (by study). Median (interquartile range [IQR]) age at enrollment was 11 (7–15) months among HUU children and 11 (8–15) months among HEU children. Lower percentages of HUU children were male (52% vs 62%), Black or African American (20% vs 47%), and Hispanic or Latino (39% vs 48%) compared to HEU children. Participant accrual by study, year, site, and HIV exposure status is shown in Supplementary Table 2.

Vaccine Infectivity

Higher infectivity of live-attenuated virus vaccines may enhance immunogenicity as a result of vaccine virus replication. Seventy-six (84%) HUU and 63 (95%) HEU study participants met the definition of having been infected by vaccine virus. Vaccine virus shedding during the 28 days after vaccination is summarized by HIV exposure status in Figure 1 (overall analysis population) and Supplementary Table 4 (by study). Peak vaccine virus titers were determined for each participant independent of study day. Among 115 (74%) children with at least 1 positive culture, the median (IQR) peak vaccine virus titer by immunoplaque assay was 3.4 (2.6–4.2) log₁₀ PFU/mL in HUU children and 3.1 (2.4–3.6) log₁₀ PFU/mL in HEU children. Vaccine shedding was detectable in nasal washes by immunoplaque assay for a median duration (IQR) of 6 (3–8) days among 66 HUU and 6 (4–8) days among 49 HEU children. Among 131 (84%) children from whom vaccine virus was detected by qPCR, the median (IQR) peak qPCR values were 5.8 (4.4–6.4) log₁₀ copies/mL in HUU children and 5.1 (3.9–5.9) log₁₀ copies/mL in HEU children. When determined using qPCR, viral shedding was detected for a median (IQR) of 10 (8–12) days among 71 HUU children and 8 (3.5–11.5) days among 60 HEU children.

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.

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Vaccine Immunogenicity

RSV serum antibody titers measured prior to and 56 days after vaccination are shown by HIV exposure status in the overall analysis population and by study in Figure 2. Lower percentages of HUU children than HEU children had serum RSV-PRNT₆₀ (62% vs 88%) and anti-RSV F IgG antibodies (19% vs 30%) prior to vaccination that were below the LLD (Supplementary Table 5). Specifically, HUU children had baseline RSV-PRNT₆₀ titers (expressed on the reciprocal log₂ scale) that were, on average, 0.72 (95% confidence interval [CI], .30–1.13) higher than those observed among HEU children adjusting for age, sex, and vaccine candidate (Table 2). Similarly, in adjusted analyses, baseline anti-RSV F IgG titers were, on average, 1.13 (95% CI, .36–1.90) higher among HUU children than among HEU children. In contrast, serum antibody titers after vaccination were generally lower among HUU children than among HEU children. At 56 days after vaccination, serum RSV-PRNT₆₀ (adjusted mean difference: −0.55 [95% CI, −1.03 to −.07]) and anti-RSV F IgG (adjusted mean difference: −0.82 [95% CI, −1.51 to −.14]) titers were lower for HUU children compared to HEU children adjusting for age, sex, vaccine candidate, and the antibody titer prior to vaccination (Table 2). HUU children generally had smaller increases in both serum RSV-PRNT₆₀ and anti-RSV F IgG antibodies after vaccination than HEU children in both the overall analysis population and by study (Supplementary Figure 1). Overall, lower percentages of HUU children than HEU children had ≥4-fold increases in serum RSV-PRNT₆₀ (67% vs 88%) and anti-RSV F IgG antibodies (70% vs 89%) between prior to and 56 days after vaccination. Similar results were obtained when analyses were limited to children with serum RSV-PRNT₆₀ or anti-RSV F IgG antibodies below the LLD prior to vaccination (Supplementary Table 6).

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.

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Differences in vaccine-elicited antibody responses were also observed based on serum antibody titers prior to vaccination irrespective of HIV exposure status. Compared to children with detectable antibody titers at baseline, a higher percentage of children with undetectable titers had a ≥4-fold increase in serum RSV-PRNT₆₀ (89% vs 41%) and anti-RSV F IgG (95% vs 73%) between prior to and 56 days after vaccination.

RSV Detections and Antibody Titers During the RSV Surveillance Period

The prevalence of symptomatic or asymptomatic wild-type RSV infection during the RSV surveillance period is summarized in Supplementary Table 7. Among children with complete data during the surveillance period, 25 of 60 (42%) HEU children and 32 of 86 (37%) HUU children had evidence of wild-type RSV infection. The prevalence of wild-type RSV infection was lower among children who had ≥4-fold increases in serum RSV-PRNT₆₀ (30% vs 65%) or anti-RSV F IgG antibodies (32% vs 65%) between prior to and 56 days after vaccination, compared with children who had <4-fold increases in these antibodies with vaccination. Fourteen (10%) children, including 7 (12%) HEU and 7 (8%) HUU, had RSV detected by culture or qPCR from a nasal wash obtained during an illness visit. An additional 43 participants had evidence of wild-type RSV infection during the RSV surveillance period on the basis of a ≥4-fold increase in serum RSV-PRNT₆₀ (n = 38) or anti-RSV F IgG antibodies (n = 42). The distribution of changes in serum antibody titers during the RSV surveillance period is shown in Figure 3. The distributions were bimodal, with 1 peak centered around an antibody increase of 5 on the reciprocal log₂ scale, corresponding to a 32-fold increase in antibody titers, and a larger peak centered around no change in antibody titer. These peaks correspond with those in the distributions of changes in antibody titers observed among participants who did or did not have RSV detected at an illness visit during the RSV surveillance period. Distributions of antibody changes were generally similar among HUU and HEU children.

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.

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DISCUSSION

Analyzing pooled data from clinical trials of 7 live-attenuated RSV vaccine candidates conducted among children with serum RSV-neutralizing titers of <1:40 demonstrated that these vaccines had high infectivity and immunogenicity among HEU children. Compared to HUU children, HEU children had lower RSV serum antibody titers prior to vaccination but mounted robust humoral immune responses to vaccination. Taken together, these results suggest that HIV exposure is unlikely to substantively affect the immunogenicity of live-attenuated RSV vaccines among young children.

Children were eligible for these trials if they had a RSV-neutralizing serum antibody titer <1:40 at screening. Within this study population, considered RSV-seronegative per the study protocols, serum RSV antibodies prior to vaccination were lower among HEU children than among HUU children. In particular, HEU children had lower baseline titers of RSV-neutralizing antibodies and IgG antibodies to the RSV F glycoprotein compared to HUU children, with higher percentages of HEU children having undetectable titers of these antibodies than HUU children. Prior studies demonstrated that HEU newborns acquire lower titers of maternal antibodies to several common bacterial and viral pathogens, including Streptococcus pneumoniae, Haemophilus influenzae type B (Hib), and RSV [12–14, 27–29]. The available data suggest that this may relate both to lower pathogen-specific serum antibody titers among pregnant women with HIV and impaired transplacental transfer of antibodies to their newborns [13, 14, 28–30]. In a study conducted among 316 mother–newborn dyads in Botswana, lower placental transfer of RSV antibodies to newborns was observed from women with HIV, although maternal viral suppression was associated with more effective antibody transfer to HEU infants [14]. Similarly, among 240 mother–newborn dyads in South Africa, HEU infants had lower RSV serum antibody titers than HUU infants; maternal hypergammaglobulinemia was more common in women living with HIV than in women without HIV (90% vs 10%) and was associated with lower RSV antibody transfer [13].

Most, but not all, prior studies reported that HEU children have similar or superior humoral immune responses to vaccination than HUU children [12, 31–34]. Jones and colleagues demonstrated that HEU children developed comparable vaccine-elicited antibody titers to pertussis and Hib and higher antibody titers to S pneumoniae and pertussis than HUU children despite having lower titers of antibodies to these pathogens at birth [12]. Similarly, a meta-analysis of 27 studies that evaluated the immunogenicity of live-attenuated measles vaccines reported similar quantitative antibody responses among HUU and HEU children [33]. In contrast, Abramczuk and colleagues reported that HEU children were more likely to be nonresponders to hepatitis B vaccine and developed lower antibody titers to tetanus toxoid than HUU children [34]. In the current study, the intranasally administered live-attenuated RSV vaccines tended to be more immunogenic among HEU children than HUU children in the absence of differences in vaccine infectivity and the magnitude or duration of vaccine shedding.

The interference of passively acquired antibodies with serum antibody responses to live vaccines has been recognized for >50 years. Some of the first data to demonstrate this phenomenon were from studies of infants receiving live-attenuated measles vaccine in which the persistence of maternal measles antibodies was implicated in the failure of some infants to develop appropriate vaccine-elicited humoral immune responses [35, 36]. Subsequent studies reported that preexisting maternal antibodies can also interfere with serum antibody responses to inactivated vaccines, while demonstrating that this effect varies based on the vaccine antigen for both live and inactivated vaccines. Preexisting antibodies were demonstrated to interfere with the development of serum antibodies following live-attenuated rubella vaccine among children 15 months of age [37], whereas this was not observed with live-attenuated mumps vaccine among infants 6, 9, or 12 months of age [38]. Similarly, preexisting maternal antibodies interfered to a greater extent with the serum antibody responses to inactivated vaccines for tetanus (8, 12, and 16 weeks of age) and pneumococcus (8 and 16 weeks of age) than for Hib (8, 12, and 16 weeks of age) [39], while maternal antibody interference was observed for whole-cell but not acellular pertussis vaccines administered at 2, 4, and 6 months of age [40]. Among the children 6 to <25 months of age with serum RSV 60% plaque neutralizing titers of <1:40 at screening included in this study, the proportion with a ≥4-fold rise in antibody titers following vaccination was lower among participants with detectable antibody titers prior to vaccination compared to those with undetectable prevaccination antibodies. The lower RSV antibody titers at baseline among HEU children likely contribute to their higher RSV antibody titers after vaccination; however, HEU children had higher antibody titers 56 days after vaccination even after adjustment for the antibody titer prior to vaccination. This difference in vaccine-elicited antibody titers by HIV exposure status was also observed in analyses limited to children with undetectable serum antibodies prior to vaccination. Taken together, these data suggest that factors in addition to the titers of maternally derived antibodies at the time of vaccination contribute to the superior quantitative serum antibody responses of HEU children to intranasal, live-attenuated vaccines.

In a prior post hoc analysis of combined results from several phase 1 studies of live-attenuated RSV vaccines, including some studies included in the present analysis, a ≥4-fold rise in serum RSV-neutralizing antibodies following intranasal vaccination was identified as a potential predictor of vaccine efficacy [41]. This analysis also suggested that a ≥4-fold rise in serum RSV-neutralizing antibodies could be considered both a direct mediator of protection and a marker for priming of other protective immune responses, such as systemic and mucosal T-cell responses or mucosal antibody responses following live-attenuated RSV vaccination [41]. Consistent with this prior study, a lower proportion of children who had a ≥4-fold rise in serum RSV-neutralizing antibodies with vaccination had evidence of wild-type RSV infection during the surveillance period than children who had less robust vaccine responses in the current analysis of data from clinical trials of 7 RSV vaccine candidates. Further analyses of the mucosal and T-cell responses following intranasal vaccination with live-attenuated RSV vaccines in the presence of residual maternal or passive RSV antibodies would be needed to elucidate the ability of live-attenuated RSV vaccines to prime active immune responses in the presence of preexisting RSV antibodies.

This study has several limitations. First, although analyses were adjusted for the vaccine received, data were pooled from clinical trials of 7 RSV vaccine candidates that had varied infectivity and immunogenicity. Additionally, data were unavailable for sociodemographic factors other than age and sex that have the potential to affect immune responses to vaccination. Nasal washes were collected only on specific days after vaccination, with minor differences in the days of sample collection across studies. Thus, data on the duration of vaccine shedding should be interpreted with caution. Although HEU children had quantitatively stronger antibody responses to live-attenuated RSV vaccines compared to HUU children, these trials were not powered to evaluate if these differences in vaccine immunogenicity correlate with improved protection from RSV infection or severe disease. Finally, these studies did not evaluate or compare mucosal and T-cell immune responses among HUU and HEU children following intranasal vaccination with live-attenuated RSV vaccines.

In conclusion, pooled analyses of clinical trials data for 7 live-attenuated RSV vaccine candidates suggest that these vaccines are highly immunogenic in HEU children. Given their increased morbidity and mortality during early childhood from RSV-ALRI and other infections, HEU children should be prioritized for vaccination as the RSV vaccines currently under development become available.

Supplementary Data

Supplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

Notes

Acknowledgments. We thank the study participants and families who participated in each of the clinical trials for their invaluable contribution to this research. We also thank the members of the National Institute of Allergy and Infectious Diseases Division of Clinical Research Data and Safety Monitoring Board. We acknowledge members of the IMPAACT P1114, 2000, 2011, 2012, 2013, and 2018 protocol teams for their expert contributions. Finally, we thank the dedicated site investigators and research professionals at the following institutions, in alphabetical order: Ann and Robert H. Lurie Children's Hospital (Ram Yogev, Ellen Chadwick), Boston Medical Center (Ellen Cooper), Children's Hospital of Philadelphia (Richard Rutstein), Emory University School of Medicine (Paul Spearman, Andres Camacho-Gonzalez), Johns Hopkins University Center for Immunization Research (Ruth Karron), Jacobi Medical Center Bronx (Andrew Wiznia, Joanna Dobroszycki), Rush University (Mariam Aziz), St Jude Children's Research Hospital (Nehali Patel), State University of New York at Stony Brook (Sharon Nachman), Texas Children's Hospital (William Shearer, Mary Paul), University of California, Los Angeles (Jaime Deville), University of California, San Diego (Stephen Spector), University of Colorado School of Medicine (Elizabeth McFarland), and University of Southern California (Mikhaela Cielo).

Author contributions. M. S. K., C. K. C., C. P., J. L. L., R. A. K., P. L. C., and U. J. B. were responsible for the conceptualization and design of this planned analysis of existing data. C. K. C., E. J. M., R. A. K., P. L. C., and U. J. B. designed the vaccine studies that generated the infectivity and immunogenicity data, and C. K. C., E. J. M., and R. A. K. led these studies. J. L. L. and C. P. provided operational and project management support to the protocol teams and participating sites. J. C. L. and M. J. G. had access to all data and take responsibility for the data and analysis. M. S. K. and M. J. G. wrote the original draft of the manuscript. All authors were involved in reviewing and editing the manuscript and approved the final work.

Disclaimer. The content in this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Financial support. Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network was provided by the National Institute of Allergy and Infectious Diseases with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health, all components of the National Institutes of Health, under award numbers UM1AI068632 (IMPAACT Leadership and Operations Center), UM1AI068616 (IMPAACT Statistical and Data Management Center), and UM1AI106716 (IMPAACT Laboratory Center), and by contract number HHSN275201800001I. M. S. K. was supported by a National Institutes of Health Career Development Award (K23-AI135090). U. J. B. and P. L. C. were supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, and in part by a Collaborative Research and Development Agreement with Sanofi.

References

Author notes