Secondary Logo

Journal Logo

Safety and immunogenicity of a live attenuated pentavalent rotavirus vaccine in HIV-exposed infants with or without HIV infection in Africa

Levin, Myron J.; Lindsey, Jane C.; Kaplan, Susan S.; Schimana, Werner; Lawrence, Jody; McNeal, Monica M.; Bwakura-Dangarembizi, Mutsa; Ogwu, Anthony; Mpabalwani, Evans M.; Sato, Paul; Siberry, George; Nelson, Margaret; Hille, Darcy; Weinberg, Geoffrey A.; Weinberg, Adriana

doi: 10.1097/QAD.0000000000001258
CLINICAL SCIENCE
Free
SDC

Objective: Although many HIV-infected (HIV+) and HIV-exposed but uninfected (HEU) infants have received live rotavirus vaccines since the WHO recommended universal administration of these vaccines to infants, there has been limited prospective information on their safety and immunogenicity in either group of infants.

Design/methods: We performed a randomized, double-blinded, placebo-controlled trial of the safety and immunogenicity of oral pentavalent rotavirus vaccine (RV5) administered to HIV+ and HEU infants in four African countries. Ninety-three percent of HIV+ infants were receiving antiretroviral therapy prior to vaccination. Participants were followed for safety. Immune responses were measured 14 days after three doses of RV5, including serum antirotavirus neutralizing and IgA antibodies, IgA antibody in stool, and antirotavirus memory B and T-cell FluoroSpot. Shedding of RV5 in stool was monitored.

Results: A total of 76 HIV+ and 126 HEU infants were enrolled from 2009 to 2013. No significant differences were found in adverse event rates, including grade 3 events, between RV5 and placebo recipients, for either HIV+ or HEU infants. The proportion of antirotavirus IgA responders (at least three-fold increase from baseline) after RV5 administration was 81% in both HIV+ and HEU infants, which was approximately 2.5-fold higher than in placebo recipients (P < 0.001). Neutralizing antibody responses to three of five serotypes were significantly higher after RV5 regardless of HIV status, and those of HIV+ infants were equal or greater than responses of HEU infants to all five serotypes. Only one HIV+ RV5 recipient had RV5 isolated from stool.

Conclusion: RV5 was immunogenic in both HIV+ and HEU infants and no safety signals were observed.

Supplemental Digital Content is available in the text

aSection of Pediatric Infectious Diseases, Departments of Pediatrics and Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado

bCenter for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, Massachusetts

cMerck & Co, Inc., Kenilworth, New Jersey, USA

dSection of Health Promotion, Department of Health and Environment, Municipality of Munich, Munich, Germany

ePfizer Inc., Collegeville, Pennsylvania

fDivision of Infectious Diseases, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA

gDepartment of Paediatrics and Child Health, University of Zimbabwe College of Health Sciences, Harare, Zimbabwe

hFormerly Harvard AIDS Institute, Gaborone, Botswana; currently Trinity Medical Centre, Port Adelaide, South Australia, Australia

iDepartment of Pediatrics and Child Health, University Teaching Hospital, Lusaka, Zambia

jFormerly Maternal Adolescent and Pediatric Research Branch, NIAID, NIH, Rockville; currently Office of AIDS Research, NIH

kMaternal and Pediatric Infectious Disease Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, Maryland

lDepartment of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York

mSection of Pediatric Infectious Diseases, Departments of Pediatrics, Medicine, and Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.

Correspondence to Myron J. Levin, University of Colorado Anschutz Medical Campus, 401 – Mail Stop C227, 1784 Racine Street, Aurora, CO 80045, USA. Tel: +1 303 724 2451; fax: +1 303 724 7909; e-mail: myron.levin@ucdenver.edu

Received 29 April, 2016

Revised 26 May, 2016

Accepted 27 May, 2016

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.AIDSonline.com).

Back to Top | Article Outline

Introduction

Rotavirus is a major cause of infant diarrheal morbidity and mortality worldwide [1,2]. Live attenuated rotavirus vaccines reduce rotavirus-related disease in healthy children in resource-rich and resource-limited countries [3–5]. Diarrheal disease is a major cause of sickness and death in HIV-infected (HIV+) children; some studies report that rotavirus infection is more severe in HIV+ children [5–9]. Although many HIV+ infants have received live rotavirus vaccines since the WHO recommendation for these vaccines, the efficacy of rotavirus vaccines for HIV+ infants has not been determined [10–12]. Information on the safety and immunogenicity of rotavirus vaccines in HIV+ infants is limited to approximately 100 infants who received the monovalent rotavirus vaccine (Rotarix, GlaxoSmithKline, Research Triangle Park, North Carolina, USA; RV1) [12,13], and less than 50 infants who received the pentavalent rotavirus vaccine (RotaTeq, Merck & Co., Inc.; RV5) [14,15]. Additional information about rotavirus vaccines in HIV+ infants is desirable because protective antibody responses can be impaired in infants with untreated HIV infection [16–19], and robust responses may not be achieved even when vaccine is administered after initiating antiretroviral therapy (ART) early in life [18,20–22]. This may be more problematic in resource-poor countries where rotavirus vaccines induce lower titers of rotavirus-specific antibody and vaccine efficacy is lower than in resource-rich countries [23]. Moreover, although HIV+ infants may benefit from rotavirus vaccines, these vaccines have been implicated in prolonged gastroenteritis with persistent shedding of vaccine-strain virus in infants with severe immune deficiency, and other live viral vaccines have caused disease in children with advanced HIV infection [24–27]. Information about rotavirus vaccination of infants who are HIV exposed but uninfected (HEU) is also desirable, as HEU infants have an excess of infectious morbidity during the first year of life [28,29]. Although HEU infants make normal levels of antibody to some vaccines typically administered during infancy [30], information on the immunogenicity and safety after administration of rotavirus vaccines to HEU infants is important, given the large number of infants born to HIV+ women.

The current report describes a randomized, placebo-controlled trial comparing the safety and immunogenicity of RV5 in HIV+ and HEU infants.

Back to Top | Article Outline

Methods

Study design

The study (P1072) sponsored by the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) network was a phase II, randomized, double-blind study of RV5 in infants born to HIV+ mothers (NCT00880698). It was approved by Institutional Review Boards of IMPAACT and appropriate institutions or national governments. Parental consent was obtained. P1072 was conducted in four African countries where rotavirus vaccine was not in the national vaccination program. Infants between 2 and less than 15 weeks old at screening were determined to be HEU or in one of three HIV+ strata (details in Supplemental Information, http://links.lww.com/QAD/A980). Infants in each stratum were randomized to receive RV5 or placebo: study dose 1 at 4 to less than 15 weeks, and study doses 2 and 3 at least 28 days after the previous vaccination, with dose 3 by 32 weeks or less. Participants were followed until 6 weeks after the last dose, with visits at 7, 14, 21, and 42 days after each dose to record clinical signs, symptoms, and new significant diagnoses. No clinical laboratory testing was required, but sites recorded laboratory results considered pertinent. Stool samples were collected at entry; at days 7, 14, 21, and 42 after dose 1; at days 7 and 21 after doses 2 and 3; and at unplanned visits for gastroenteritis. Blood for immunogenicity testing was collected at entry and 14 days after dose 3 (42 days if not collected at 14 days).

Back to Top | Article Outline

Study conduct

Shortly after the study began, the protocol was amended to require HIV+ infants to receive ART before receiving study vaccine. Six of 76 (7%) of these infants received study vaccine prior to this requirement. Enrollment was closed in participating countries when RV1 was added to national vaccine schedules (details in Supplemental Information, http://links.lww.com/QAD/A980).

Back to Top | Article Outline

Study outcomes

Safety

Laboratory values, signs, symptoms, and diagnoses were graded according to the Division of AIDS Table for Grading Severity of Adult and Pediatric Adverse Events [31]. Sites reported grade ≥1 signs, symptoms, and diagnoses. Events that were grade ≥2, and grade ≥1 targeted signs/symptoms (vomiting, fever, diarrhea, irritability), targeted diagnoses (gastroenteritis, intussusception, and diagnoses with the rotavirus organism code), and deaths were reviewed by the Core Team [study chairs, immunologist, National Institutes of Health (NIH) medical officers, and pharmaceutical representatives].

Back to Top | Article Outline

Immunogenicity

Serum antirotavirus neutralizing antibodies (SNAs): Neutralizing antibodies to type-specific outer surface proteins of RV5 (G1, G2, G3, G4, and P1A) were measured as published [32] (details in Supplemental Information, http://links.lww.com/QAD/A980).

Serum antirotavirus IgA antibody was measured by a standard enzyme immunoassay (EIA) format previously published [33] (details in Supplemental Information, http://links.lww.com/QAD/A980).

Coproantibody (stool antirotavirus IgA) was measured in stool filtrates by the methods used for serum IgA, but standardized to total IgA and reported as rotavirus antigen units per microgram of total IgA.

Back to Top | Article Outline

Antirotavirus memory B and T-cell responses (FluoroSpot)

Memory B-cell responses

Peripheral blood mononuclear cells were cryopreserved at clinical sites using a standardized protocol [34], and shipped for detection of IgG/IgA secreting cells (details in Supplemental Information, http://links.lww.com/QAD/A980).

Back to Top | Article Outline

T-cell responses

A dual color IFNγ and IL-2 ELISPOT assay (ELISPOT, FluoroSpot kit; MabTech, Nacka Strand, Sweden) was used per manufacturer's instructions (details in Supplemental Information, http://links.lww.com/QAD/A980).

Shedding of rotavirus in stool: Rotavirus in stool was initially assessed using an ELISA assay using a published commercial rotavirus antigen detection kit [35]. Positive samples were identified as vaccine or wild type with reverse transcriptase-polymerase chain reaction (RT-PCR) assays specific for rotavirus VP4, VP6, and VP7 genotypes, and infectious virus identified with a fluorescent focus assay (FFA) [35].

Back to Top | Article Outline

Statistical methods

Baseline and safety data were presented ‘as randomized’ (intent-to-treat). Immunogenicity analyses were conducted in the ‘per-protocol’ population, defined as participants completing the three as-randomized vaccinations within the required windows. Sensitivity analyses were done for safety, only including participants who received the correct vaccine, and for immunogenicity, in the intent-to-treat population. Proportions were presented with exact 95% confidence intervals and compared using Fisher's exact tests (unadjusted) and logistic regression (adjusted). Continuous outcomes were compared using Wilcoxon rank sum tests (unadjusted) and censored normal regression on log10-transformed levels adjusted for other covariates.

Back to Top | Article Outline

Safety

Proportions of participants experiencing new adverse events (appearing after the first vaccination, or increased grade reported after the first vaccination) were presented by HIV-1 stratum and vaccine group.

Back to Top | Article Outline

Immunogenicity

Serum antibodies

Measurements outside the lower limit of quantitation (LLOQ) or upper limit of quantitation of each assay were set to those limits. The primary outcome measure was predefined as at least three-fold increase achieved postdose 3 (PD3) in SNA and IgA over the entry value. If the entry value was above one-third of the upper limit of quantitation, the infant was not classified as a responder and was excluded from analysis. The secondary outcome was antibody level PD3.

Back to Top | Article Outline

B and T-cell responses

IgA and IgG memory B cells were measured in samples from a randomly chosen subset that received three vaccinations and met viability assay criteria. Each response was measured in duplicate wells at entry, 14, and 42 days PD3. If two measurements were available, the analysis unit was the mean of both responses. T-cell responses were calculated as the difference between WC3-containing wells and the MA104 controls. Negative differences and differences of zero were set to 0.1 to allow log transformation for analysis. Participants were classified as responders if they achieved at least two-fold increase over entry levels by either 14 or 42 days PD3.

Coproantibodies: Measurements below the LLOQ were set to the LLOQ. Spearman correlations were calculated on PD3 levels of coproantibodies and serum IgA antibodies.

Vaccine virus in stool: Numbers of infants with EIA-positive stool after each study dose were reported. The EIA-positive samples that were FFA+ and RT-PCR+ for VP6 were summarized.

Analyses were conducted in Statistical Analysis System Version 9.4; SAS Institute Inc., Cary, North Carolina, USA).

Back to Top | Article Outline

Results

Accrual and baseline characteristics

Between December 2009 and October 2013, 202 infants (126 HEU, 76 HIV+) were enrolled [(79% of the target for HEU, 48% for HIV+ (Table 1)]. HIV+ infants were less likely to have received prophylaxis to prevent HIV transmission [prevention of mother-to-child transmission (PMTCT)] and their mothers were less likely to have received ART. The Consolidated Standard for Reporting Trials (CONSORT) diagram (Supplemental Figure 1, http://links.lww.com/QAD/A980) indicates the number of participants in each treatment arm; 188 (93%) received study vaccine per protocol. Accrual was low in Tanzania because of late approval of the study by the national review board and in Zambia and Tanzania because of early adoption of a national recommendation for rotavirus vaccination.

Table 1

Table 1

Back to Top | Article Outline

Safety

Adverse events and targeted signs/symptoms are summarized in Table 2. Proportions of participants with adverse events tended to be higher in HIV+ infants, but this was true regardless of exposure to RV5. There was no statistically significant difference in proportions of HIV+ or HEU participants receiving either RV5 or placebo, or within CD4% strata for the HIV+ infants (Table 2; Supplemental Tables 1 and 2, http://links.lww.com/QAD/A980). Event rates within 7 days of vaccination were similar. CD4% increased and HIV RNA viral load decreased significantly in HIV+ infants from entry to study end in both RV5 and placebo recipients, with no differences in the magnitude of change in CD4% or proportions of participants with HIV-1 RNA 400 copies/ml or less between vaccine groups.

Table 2

Table 2

Three HIV+ infants (one RV5, two placebo) died of pneumonia 3–4 weeks after the first study dose. These were deemed by the site and Core Team as not, or probably not, related to study vaccine. Eight HIV+ infants (five RV5, three placebo) and five HEU infants (two RV5, three placebo) were hospitalized during the study. Reasons for hospitalization were gastroenteritis (4), pneumonia (4), malaria (1), measles (1), febrile seizures (1), and no diagnosis recorded (2). There were no statistically significant differences between RV5 and placebo in changes from baseline in WHO weight or height-for-age z-scores. HIV test results were available for 121/126 HEU infants at least 14 days PD3; all were negative.

Back to Top | Article Outline

Rotavirus serum antibody responses

The proportion of antirotavirus IgA responders (at least three-fold increase from baseline) reached 81% in both HIV+ and HEU recipients of RV5 and was approximately 2.5 to three-fold higher than in placebo recipients (Table 3). Response rates in the SNA assay varied by serotype (∼20–60%). Proportions of RV5 recipients responding to each serotype was consistently higher, for both HIV+ and HEU infants, compared with placebo recipients. For all SNA assays except P1A, the proportion of RV5 responders was higher in HIV+ compared with HEU infants. This was likely because of higher levels of transplacentally transferred maternal antibodies in HEU infants, which limited their ability to achieve a three-fold increase in SNA antibody after vaccination. This is demonstrated in Table 4 and Supplemental Figure 2, http://links.lww.com/QAD/A980, which show that median levels for each specific antibody were higher in the HEU infants at baseline (P ≤ 0.001 for all SNA). Antibody levels were consistently higher in RV5 recipients, for both HIV+ and HEU infants compared with placebo recipients. Importantly, both IgA and SNA postvaccination antibody levels were not significantly different by HIV status (Table 4 and Supplemental Figure 2, http://links.lww.com/QAD/A980).

Table 3

Table 3

Table 4

Table 4

Adjusted analyses were performed to identify potential predictors of response and of levels achieved PD3 among RV5 recipients. Covariates included infant ever breastfed, oral polio vaccine coadministered with the first or with three vaccinations, infant exposure to prophylaxis to prevent PMTCT, and any detection of rotavirus antigen in stool between the first and last doses. For HIV+ infants, additional covariates included screening CD4%, entry HIV-1 RNA, infant exposure to PMTCT, and number of days on ART at entry. Adjusted analyses for each of these factors had little effect on the magnitude or statistical significance of the odds of responding to RV5 relative to estimates from unadjusted models (data not shown). No covariates were consistently associated with the odds of responding or with PD3 levels across immunologic assays. Because of the number of models fit and the lack of consistent findings across outcomes, we do not report the few statistically significant findings.

Back to Top | Article Outline

Rotavirus coproantibodies

Median (Q1, Q3) levels of coproantibodies at entry were higher in HIV+ than in HEU infants, but the difference was not statistically significant (P = 0.13; Table 4). Postvaccination levels were significantly higher in RV5 recipients compared with placebo recipients in HEU, but not HIV+ infants. Coproantibody levels were not significantly different in RV5 recipients between the HIV+ and HEU infants. Coproantibody and serum antibody levels PD3 were positively correlated [Spearman correlation = 0.55 for HEU (P < 0.001); 0.39 for HIV+ (P = 0.040)].

Back to Top | Article Outline

Cellular immunity

At entry, rotavirus-specific B and T-cell immunity were very low (median = 0.1; Table 5) and did not differ by HIV status. After vaccination, IgA B-cell memory was significantly higher in HIV+ infants receiving RV5 compared with placebo recipients (P = 0.04; Table 5), although this was based on the distribution of values in the third quartile and the magnitude of the difference was small. There were no significant differences in HEU infants. IgG memory B-cell responses did not appreciably increase after vaccination. There were no statistically significant differences in proportions of participants with at least two-fold increase in WC3-specific memory B or T cells at PD3 compared with entry, either by vaccine group within HIV status or by HIV status in RV5 recipients (Table 5). These results should be interpreted with caution, because at entry, most participants had no secreting T or B cells, so that small increases were considered a response. PHA responses were poor and did not differ between vaccine groups or by HIV status in RV5 recipients (data not shown).

Table 5

Table 5

Back to Top | Article Outline

Fecal shedding

All participants had at least one stool sample collected after the first vaccination (Supplemental Table 3, http://links.lww.com/QAD/A980). Nine of 99 (9%) RV5 recipients after the first dose, and one of 98 after the second dose, had at least one stool sample positive for rotavirus by EIA. Across all samples at all times, rotavirus was detected by EIA in 13.0% (eight of 62; one positive after both dose 1 and 2) of the HEU infants and in 2.7% (one of 37) of the HIV+ infants who received RV5; for placebo recipients, these percentages were 6.3% (four of 64) for the HEU and 7.7% (three of 39) for the HIV+ infants.

All EIA-positive samples were evaluated by FFA to determine if infectious rotavirus was present, and by RT-PCR to determine the rotavirus source, and were further characterized by VP4 and VP7 type. Only one of 37 (2.7%) HIV+ RV5 recipients shed FFA+ vaccine-type rotavirus after the first vaccination. No shedding was detected in any infant after the third vaccination.

Back to Top | Article Outline

Discussion

There was no evidence that RV5 was associated with excess adverse signs or symptoms in either HIV+ or HEU infants. Two of three deaths in HIV+ infants occurred in placebo recipients. One death and eight hospitalizations occurring in HIV+ infants were attributed to infectious causes common in these infants. Moreover, vaccination did not alter the CD4% or viral load response to ART in RV5 recipients during the study. Although limited in number, no HEU recipients of RV5 acquired HIV infection during the study. The prospective safety information collected is reassuring and consistent with previously published information for both rotavirus vaccines.

Virus-specific serum IgA antibody responses after RV5 vaccination were not significantly different in HIV+ and HEU infants, both in terms of three-fold rise and postvaccination titer. Of note, levels of serum IgA, which is not transplacentally transferred, did not differ before vaccination between HEU and HIV+ participants. This is important because serum IgA has been associated with protection against symptomatic disease and disease severity after natural exposure [36–39], and serum IgA correlated with protection in a study of an experimental rhesus rotavirus vaccine [33]. The magnitude of IgA antibody induced by RV5 in the current study was almost identical, utilizing the same laboratory assay, to that reported in a large trial of the safety and efficacy of RV5 in Africa [15]. A systematic review of rotavirus vaccine trials in settings stratified by rate of childhood mortality (as a marker for medical and other resources) found that postvaccination IgA antibody titer was lower in countries with higher childhood mortality and that titer correlated with lower efficacy [40]. In this context, our data suggest that the efficacy of the RV5 vaccine will not only be lower in HIV+ or HEU compared with HIV-unexposed African infants, but also not as high as in infants in the United States.

Coproantibodies were significantly induced by RV5 in HEU infants only, although there were no significant differences in PD3 levels between HIV+ and HEU infants after RV5 administration. The correlation of coproantibodies with protection is less clear in adult challenge models and in relation to natural infection [41,42].

The assessment of SNA responses also demonstrated an increase in virus-specific antibody levels after RV5. These differed by antigen and were especially strong against G1 and G4. Variable response by antigen was previously reported from the US and African efficacy studies, where G1 and G4 seroresponses were also most prominent [15,43]. SNA levels PD3 in RV5 recipients were not statistically different between HIV+ and HEU infants. SNA levels have also been associated with protection in clinical trials, including an analysis of 1857 study participants in phase II/III trials of RV5 that correlated titers of SNA against G1 with protection against rotavirus gastroenteritis [41,44]. Most vaccinees were breastfed (63%) and most received oral polio vaccine (75% for dose 1, 59% for dose 2) concomitant with RV5. With the caveat of the limited sample size, we did not find that either of these interfered with the immune response to RV5, which is consistent with the published literature [45,46]. In addition, there was no discernible effect of entry CD4% or viral load on antibody responses.

This is the first study of an orally administered live vaccine to HIV+ infants that stipulated ART prior to immunization. At the time of the first dose of RV5, 92% of the 37 HIV+ infants were receiving ART and only one had a CD4% less than 15. These were likely important factors in the responses to RV5, which significantly increased three different types of antibody utilizing three different laboratory methods. The second and third RV5 doses were administered after an interval of at least 1 and 2 months, respectively, of beginning ART, which may have contributed to the similar responses in both HIV+ and HEU infants. Moreover, where comparisons can be made, antibody titers after RV5 were similar to those reported in prior trials in unexposed and uninfected infants [15,43,44]. The paucity of shedding of RV5 after vaccination is additional evidence of immune preservation in our study participants.

HIV+ and HEU infants responded equally in all three immune assays. HEU infants were considered an appropriate proxy for healthy children, as the effectiveness of RV1 was the same in HEU and HIV-unexposed infants in a prior study [12]. However, the data on the adequacy of the HEU responses to vaccines is still mixed [30,47]. In the past, responses reported after childhood vaccinations were impaired in HIV+ infants, especially in those with low CD4%, high HIV viral load, and short duration of ART [17,19]. This is why current recommendations are to reimmunize HIV+ children who had been immunized before HIV therapy, but to delay this until 3 months after beginning ART [47,48]. This would not be feasible for rotavirus vaccines because of the need to provide protection early in infancy. The current study suggests that very early administration of rotavirus vaccines may be effective when given concomitant with ART. Furthermore, considering that in this study most infants received study vaccine at 80–90 days of life, and that they had only been on ART for a median of 4 days, the outcome measures might have been even better if ART was started earlier.

There is also evidence that the magnitude and duration of immune memory is impaired when immunization is attempted in severely immune suppressed HIV+ children, and that immune memory may be preserved when ART is started in infancy [47,49]. In this study, HIV+ RV5 recipients developed significantly higher numbers of IgA memory B cells compared with placebo recipients, although the magnitude of this difference was not large. Differences did not reach significance among HEU and there were no other statistically significant differences in PD3 levels of B or T-cell-mediated immune responses across vaccine or HIV status groups. Overall, cell-mediated immune responses to RV5 were of low magnitude. This was also true of nonspecific responses, such as IFNγ and IL-2 spot-forming cells after phytohemagglutinin stimulation, and total IgG and IgA-secreting B cells (data not shown), suggesting that immaturity of the immune system contributed to the low cellular responses to RV5. In addition, other factors might have contributed to the low rotavirus vaccine-specific cell-mediated immune responses, including homing to the gut in the immediate phase after immunization or acute rotavirus vaccine infection as was observed in acute rotavirus infection [50]. Whether RV5 establishes persistent memory is an important question, as protection into the second year of life is essential, especially in resource-poor countries. Assuming that ART is started shortly after birth in HIV+ infants, as in this study, the third dose will be given after a long period of ART. This might influence persistence, as suggested by a report that a third dose of RV1, compared with the recommended two doses for that vaccine, resulted in higher serum IgA titers and significantly greater efficacy in the second year postvaccination in a developing world setting [51,52].

The relatively small sample size of this study and the absence of an HIV-unexposed control group limit our ability to make definitive statements about RV5 in HIV+ infants. Nevertheless, we found RV5 to be immunogenic in this placebo-controlled, randomized clinical trial and no safety signal was apparent. In the future, accurate assessment of the safety and value of rotavirus vaccines in HEU and HIV+ infants will require larger-scale effectiveness studies, as performing placebo-controlled efficacy trials will no longer be ethical.

Back to Top | Article Outline

Acknowledgements

Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) under Award Numbers UM1AI068632 (IMPAACT LOC), UM1AI068616 (IMPAACT SDMC), and UM1AI106716 (IMPAACT LC), with cofunding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Mental Health (NIMH). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

We gratefully acknowledge the contributions of the site investigators and site staff who conducted the P1072 study: Gaborone Prevention/Treatment Trials CRS: Charles Fane RN/MW, Dudu Kooreng RN, Tebogo J. Kakhu BSN, RN/MW, Loeto Mazhani MD; Molepolole Prevention/Treatment Trials CRS: Tumalano Sekoto BSN, RN/MW, Lesedi Tirelo RN, Tshepo T. Frank BPharm, Mpho Raesi BSN; Kilimanjaro Christian Medical CRS: Grace Kinabo MD, PhD, Boniface Njau MPH, Anne Buchanan MD, MPH, Janeth Kimaro RN; George Clinic CRS: Felistus Mbewe RN, BSc, Ellen Shingalili RN, Fyatilani Chirwa RN, Helen Bwalya Mulenga BPharm, MBA; Harare Family Care CRS: Tapiwa Mbengeranwa MBChB, Taurai Beta MBChB, Ethel Dauya MPH, Hilda Mujuru MBChB, MMed, MSc.

IMPAACT P1072 Study Team: Jennifer Read, MD, NICHD Medical Officer; Lisa Monte, RN, Field Representative; Debra Mérès, Pharm D, Protocol Pharmacist; Deborah Persaud, MD, Protocol virologist; Nicole Carpenti, MS, Protocol Laboratory Technologist; Heather Springer, Protocol Laboratory Coordinator.

Merck & Co., Inc. provided financial support. In addition, Barbara Heckman BS (Frontier Science and Technology Research Foundation, Inc., 4033 Maple RD., Amherst, NY 14226, USA) helped with study conduct and manuscript preparation, Michelle Brown (Merck & Co., Inc.) contributed to the protocol development, and Jon Stek (Merck & Co., Inc.) for assistance in preparing the manuscript.

Funding for this research was provided by Merck & Co., Inc., Kenilworth, NJ, USA (sponsor) in conjunction with the International Maternal, Pediatric, and Adolescent AIDS Clinical Trials Network (IMPAACT) of the National Institute of Allergy and Infectious Diseases, NIH; National Institute of Mental Health, NIH; and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH.

Although the sponsor formally reviewed a penultimate draft, the opinions expressed are those of the authors and may not necessarily reflect those of the sponsor, IMPAACT, or NIH. All coauthors approved the final version of the manuscript.

No author was paid for their work on this manuscript.

Study identification: IMPAACT P1072 (V260–011).

CLINICALTRIALS.GOV identifier: NCT00880698.

Back to Top | Article Outline

Conflicts of interest

M.J.L. (chair), J.C.L. (statistician), W.S. (vice chair), M.M.M. (laboratory), Barbara Heckman (data manager), P.S. (NIAID medical officer), G.K.S. (NICHD medical officer), G.A.W. (investigator), and A.W. (immunologist) were members of the core protocol team supported by research grants.

W.S. (Tanzania), M.B.D. (Zimbabwe), A.O. (Botswana), and E.M.M. (Zambia) were site investigators for the sponsor supported by research grants.

S.S.K., J.L., M.N., and D.H. are/were employees of the sponsor and may hold stock and/or stock options from the sponsor.

Back to Top | Article Outline

References

1. Tate JE, Burton AH, Boschi-Pinto C, Steele AD, Duque J, Parashar UD. 2008 estimate of worldwide rotavirus-associated mortality in children younger than 5 years before the introduction of universal rotavirus vaccination programmes: a systematic review and meta-analysis. Lancet Infect Dis 2012; 12:136–141.
2. Parashar UD, Hummelman EG, Bresee JS, Miller MA, Glass RI. Global illness and deaths caused by rotavirus disease in children. Emerg Infect Dis 2003; 9:565–572.
3. Tate JE, Parashar UD. Rotavirus vaccines in routine use. Clin Infect Dis 2014; 59:1291–1301.
4. Atherly D, Dreibelbis R, Parashar UD, Levin C, Wecker J, Rheingans RD. Rotavirus vaccination: cost-effectiveness and impact on child mortality in developing countries. J Infect Dis 2009; 200 (suppl 1):S28–38.
5. Groome MJ, Madhi SA. Five-year cohort study on the burden of hospitalisation for acute diarrhoeal disease in African HIV-infected and HIV-uninfected children: potential benefits of rotavirus vaccine. Vaccine 2012; 30 (suppl 1):A173–A178.
6. Pavia AT, Long EG, Ryder RW, Nsa W, Puhr ND, Wells JG, et al. Diarrhea among African children born to human immunodeficiency virus 1-infected mothers: clinical, microbiologic and epidemiologic features. Pediatr Infect Dis J 1992; 11:996–1003.
7. Chhagan MK, Kauchali S. Comorbidities and mortality among children hospitalized with diarrheal disease in an area of high prevalence of human immunodeficiency virus infection. Pediatr Infect Dis J 2006; 25:333–338.
8. Cunliffe NA, Gondwe JS, Kirkwood CD, Graham SM, Nhlane NM, Thindwa BD, et al. Effect of concomitant HIV infection on presentation and outcome of rotavirus gastroenteritis in Malawian children. Lancet 2001; 358:550–555.
9. Steele AD, Cunliffe N, Tumbo J, Madhi SA, De Vos B, Bouckenooghe A. A review of rotavirus infection in and vaccination of human immunodeficiency virus-infected children. J Infect Dis 2009; 200 (suppl 1):S57–62.
10. Rotavirus vaccines. WHO position paper: January 2013. Wkly Epidemiol Rec 2013; 88:49–64.
11. Msimang VM, Page N, Groome MJ, Moyes J, Cortese M, Seheri M, et al. Impact of rotavirus vaccine on childhood diarrheal hospitalization following introduction into the South African Public Immunization Program. Pediatr Infect Dis J 2013; 32:1359–1364.
12. Groome MJ, Page N, Cortese MM, Moyes J, Zar HJ, Kapongo CN, et al. Effectiveness of monovalent human rotavirus vaccine against admission to hospital for acute rotavirus diarrhoea in South African children: a case-control study. Lancet Infect Dis 2014; 14:1096–1104.
13. Steele AD, Madhi SA, Louw CE, Bos P, Tumbo JM, Werner CM, et al. Safety, reactogenicity, and immunogenicity of human rotavirus vaccine RIX4414 in human immunodeficiency virus-positive infants in South Africa. Pediatr Infect Dis J 2011; 30:125–130.
14. Laserson KF, Nyakundi D, Feikin DR, Nyambane G, Cook E, Oyieko J, et al.. Safety of the pentavalent rotavirus vaccine (PRV), RotaTeq(®), in Kenya, including among HIV-infected and HIV-exposed infants. Vaccine 2012; 30 (Suppl 1):A61–70.
15. Armah GE, Sow SO, Breiman RF, Dallas MJ, Tapia MD, Feikin DR, et al. Efficacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries in sub-Saharan Africa: a randomised, double-blind, placebo-controlled trial. Lancet 2010; 376:606–614.
16. Arpadi SM, Markowitz LE, Baughman AL, Shah K, Adam H, Wiznia A, et al. Measles antibody in vaccinated human immunodeficiency virus type 1-infected children. Pediatrics 1996; 97:653–657.
17. Sutcliffe CG, Moss WJ. Do children infected with HIV receiving HAART need to be revaccinated?. Lancet Infect Dis 2010; 10:630–642.
18. Abzug MJ, Qin M, Levin MJ, Fenton T, Beeler JA, Bellini WJ, et al. Immunogenicity, immunologic memory, and safety following measles revaccination in HIV-infected children receiving highly active antiretroviral therapy. J Infect Dis 2012; 206:512–522.
19. Gnanashanmugam D, Troy SB, Musingwini G, Huang C, Halpern MS, Stranix-Chibanda L, et al. Immunologic response to oral polio vaccine in human immunodeficiency virus-infected and uninfected Zimbabwean children. Pediatr Infect Dis J 2012; 31:176–180.
20. Madhi SA, Adrian P, Cotton MF, McIntyre JA, Jean-Philippe P, Meadows S, et al. Effect of HIV infection status and antiretroviral treatment on quantitative and qualitative antibody responses to pneumococcal conjugate vaccine in infants. J Infect Dis 2010; 202:355–361.
21. Siberry GK, Patel K, Bellini WJ, Karalius B, Purswani MU, Burchett SK, et al. Immunity to measles, mumps, and rubella in US children with perinatal HIV infection or perinatal HIV exposure without infection. Clin Infect Dis 2015; 61:988–995.
22. Simani OE, Izu A, Violari A, Cotton MF, van Niekerk N, Adrian PV, et al. Effect of HIV-1 exposure and antiretroviral treatment strategies in HIV-infected children on immunogenicity of vaccines during infancy. AIDS 2014; 28:531–541.
23. Nelson EA, Glass RI. Rotavirus: realising the potential of a promising vaccine. Lancet 2010; 376:568–570.
24. Patel NC, Hertel PM, Estes MK, Estes MK, de la Morena M, Petru AM, et al. Vaccine-acquired rotavirus in infants with severe combined immunodeficiency. N Engl J Med 2010; 362:314–319.
25. Merck Co I. Patient Product Information, RotaTeq. In: Merck Co, I., editor. wwwmerckcom. online; 2013. p. 1–13.
26. GSK. Package Insert and Patient Information - Rotarix. In: Biologicals G., editor. Online: FDA; 2014: 1–22.
27. Ion-Nedelcu N, Dobrescu A, Strebel PM, Sutter RW. Vaccine-associated paralytic poliomyelitis and HIV infection. Lancet 1994; 343:51–52.
28. Mussi-Pinhata MM, Freimanis L, Yamamoto AY, Korelitz J, Pinto JA, Cruz ML, et al. Infectious disease morbidity among young HIV-1-exposed but uninfected infants in Latin American and Caribbean countries: the National Institute of Child Health and Human Development International Site Development Initiative Perinatal Study. Pediatrics 2007; 119:e694–704.
29. Koyanagi A, Humphrey JH, Ntozini R, Nathoo K, Moulton LH, Iliff P, et al. Morbidity among human immunodeficiency virus-exposed but uninfected, human immunodeficiency virus-infected, and human immunodeficiency virus-unexposed infants in Zimbabwe before availability of highly active antiretroviral therapy. Pediatr Infect Dis J 2011; 30:45–51.
30. Jones CE, Naidoo S, De Beer C, Esser M, Kampmann B, Hesseling AC. Maternal HIV infection and antibody responses against vaccine-preventable diseases in uninfected infants. JAMA 2011; 305:576–584.
31. Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events Version 1.0. December, 2004; Clarification August 2009. National Institute of Allergy and Infectious Diseases; 2009.
32. Knowlton DR, Spector DM, Ward RL. Development of an improved method for measuring neutralizing antibody to rotavirus. J Virol Methods 1991; 33:127–134.
33. Ward RL, Knowlton DR, Zito ET, Davidson BL, Rappaport R, Mack ME. Serologic correlates of immunity in a tetravalent reassortant rotavirus vaccine trial. US Rotavirus Vaccine Efficacy Group. J Infect Dis 1997; 176:570–577.
34. Coordination H-HAN. HANC Procedures and SOPs. 03/2016 ed. Online; 2016.
35. Ward RL, Bernstein DI, Young EC, Sherwood JR, Knowlton DR, Schiff GM. Human rotavirus studies in volunteers: determination of infectious dose and serological response to infection. J Infect Dis 1986; 154:871–880.
36. Hjelt K, Grauballe PC, Paerregaard A, Nielsen OH, Krasilnikoff PA. Protective effect of preexisting rotavirus-specific immunoglobulin A against naturally acquired rotavirus infection in children. J Med Virol 1987; 21:39–47.
37. O’Ryan ML, Matson DO, Estes MK, Pickering LK. Antirotavirus G type-specific and isotype-specific antibodies in children with natural rotavirus infections. J Infect Dis 1994; 169:504–511.
38. Desselberger U, Huppertz HI. Immune responses to rotavirus infection and vaccination and associated correlates of protection. J Infect Dis 2011; 203:188–195.
39. Velazquez FR, Matson DO, Guerrero ML, Shults J, Calva JJ, Morrow AL, et al. Serum antibody as a marker of protection against natural rotavirus infection and disease. J Infect Dis 2000; 182:1602–1609.
40. Patel M, Glass RI, Jiang B, Santosham M, Lopman B, Parashar U. A systematic review of antirotavirus serum IgA antibody titer as a potential correlate of rotavirus vaccine efficacy. J Infect Dis 2013; 208:284–294.
41. Franco MA, Angel J, Greenberg HB. Immunity and correlates of protection for rotavirus vaccines. Vaccine 2006; 24:2718–2731.
42. Ward RL, Bernstein DI, Shukla R, Young EC, Sherwood JR, McNeal MM, et al. Effects of antibody to rotavirus on protection of adults challenged with a human rotavirus. J Infect Dis 1989; 159:79–88.
43. Vesikari T, Matson DO, Dennehy P, Van Damme P, Santosham M, Rodriguez Z, et al. Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine. N Engl J Med 2006; 354:23–33.
44. Liu GF, Hille D, Ngai A, Lawrence J, Goveia M. Correlation between immunogenicity and efficacy from clinical trials of the pentavalent rotavirus vaccine [Abstract 283].Proceedings of the 31st Annual Meeting of the European Society for Paediatric Infectious Diseases. 2013 May 28–June 1, 2013; Milan, Italy.
45. Ciarlet M, Sani-Grosso R, Yuan G, Liu GF, Heaton PM, Gottesdiener KM, et al. Concomitant use of the oral pentavalent human-bovine reassortant rotavirus vaccine and oral poliovirus vaccine. Pediatr Infect Dis J 2008; 27:874–880.
46. Goveia MG, DiNubile MJ, Dallas MJ, Heaton PM, Kuter BJ. Efficacy of pentavalent human-bovine (WC3) reassortant rotavirus vaccine based on breastfeeding frequency. Pediatr Infect Dis J 2008; 27:656–658.
47. Simani OE, Adrian PV, Violari A, Kuwanda L, Otwombe K, Nunes MC, et al. Effect of in-utero HIV exposure and antiretroviral treatment strategies on measles susceptibility and immunogenicity of measles vaccine. AIDS 2013; 27:1583–1591.
48. Rigaud M, Borkowsky W, Muresan P, Weinberg A, Larussa P, Fenton T, et al. Impaired immunity to recall antigens and neoantigens in severely immunocompromised children and adolescents during the first year of effective highly active antiretroviral therapy. J Infect Dis 2008; 198:1123–1130.
49. McLean HQ, Fiebelkorn AP, Temte JL, Wallace GS. Prevention of measles, rubella, congenital rubella syndrome, and mumps, 2013: summary recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2013; 62:1–34.
50. Pensieroso S, Cagigi A, Palma P, Nilsson A, Capponi C, Freda E, et al. Timing of HAART defines the integrity of memory B cells and the longevity of humoral responses in HIV-1 vertically-infected children. Proc Natl Acad Sci U S A 2009; 106:7939–7944.
51. Parra M, Herrera D, Jácome MF, Mesa MC, Rodríguez LS, Guzmán C, et al. Circulating rotavirus-specific T cells have a poor functional profile. Virology 2014; 468–470:340–350.
52. Madhi SA, Kirsten M, Louw C, Bos P, Aspinall S, Bouckenooghe A, et al. Efficacy and immunogenicity of two or three dose rotavirus-vaccine regimen in South African children over two consecutive rotavirus-seasons: a randomized, double-blind, placebo-controlled trial. Vaccine 2012; 30 (suppl 1):A44–51.
Keywords:

HIV exposed; HIV infection; immunogenicity; infants; rotavirus; rotavirus vaccine; safety

Supplemental Digital Content

Back to Top | Article Outline
Copyright © 2017 Wolters Kluwer Health, Inc.