*Makerere University—Johns Hopkins University Research Collaboration, Kampala, Uganda
†Family Health International 360, Research Triangle Park, NC
‡Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD
§Vaccine and Infectious Disease Division, Statistical Center for HIV/AIDS Research & Prevention, Fred Hutchinson Cancer Research Center, Seattle, WA
||School of Public Health and Health Services, Sanofi Pasteur, Swiftwater, PA
¶Department of Prevention Science, Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, MD
#George Washington University School of Public Health and Health Services, Washington, DC
Correspondence to: Kenneth Kintu, MBCHB, Makerere University—Johns Hopkins University Research Collaboration, PO Box 23491, Kampala, Uganda (e-mail: email@example.com).
Supported by the HIV Prevention Trials Network 027 study was funded by the US National Institutes of Health, initially through the HIV Prevention Trials Network and later through the International Maternal Pediatric Adolescent AIDS Clinical Trials Group. The HIV Prevention Trials Network (U01AI46749 and U01 AI48054) has been funded by the National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Drug Abuse, and National Institute of Mental Health. The International Maternal Pediatric Adolescent AIDS Clinical Trials Group (U01AI068632) has been funded by National Institute of Allergy and Infectious Diseases, National Institute of Child Health and Human Development, and National Institute of Mental Health. The study product was provided for free by Sanofi Pasteur.
Presented at AIDS Vaccine 2010, September 28 to October 1, 2010, Atlanta, GA; CROI 2008, February 3–6, 2008, Boston, MA; The Fourth Forum of the African AIDS Vaccine Programme, November 28–30, 2007; Abuja, Nigeria; AIDS Vaccine 2007, August 20–23, 2007, Seattle, WA.
The authors have no conflicts of interest to disclose.
Received September 19, 2012
Accepted November 20, 2012
In 2011, an estimated 330,000 children acquired HIV infection through mother-to-child transmission (MTCT).1 Breastfeeding carries an HIV transmission risk of around 15% when continued into the second year of life, accounting for as much as 42% of the overall risk of MTCT of HIV.2,3 However, in most developing countries, promotion of breastfeeding has been central to reducing infant mortality by providing optimal nutrition and protection against common childhood diseases.4–6
Prevention of postnatal pediatric HIV infection is now possible through the extended use of either maternal triple antiretroviral drugs (ARV) or ARV prophylaxis to infants during breastfeeding.7–12 In 2010, the World Health Organization (WHO) revised HIV prevention of mother-to-child transmission (PMTCT) and infant feeding recommendations for settings with high infant mortality to encourage HIV-infected women to continue to breastfeed for at least 12 months and receive either infant or maternal ARV prophylaxis to minimize HIV transmission and maximize infant survival.1,13 However, translating the results of those trials into practice in the field faces considerable challenges.14 These include limited coverage of adequate comprehensive PMTCT services, poor postnatal follow-up, lack of identification of HIV exposure in infants, cost, supply chain issues, adherence, and weak linkages to HIV care and treatment programs.13–15 Therefore, identification of a safe and effective HIV vaccine that could be administered to infants along with routine immunizations remains an important goal in the efforts to eliminate HIV infection in children. The study of HIV vaccines in HIV-exposed infants also has the potential to advance the global HIV vaccine research agenda and contribute to the scientific knowledge that will eventually lead to an effective HIV vaccine.
Recombinant canarypox-vectored ALVAC-HIV vaccine products have a long history of use in studies with large numbers of adults in various countries and a small number of infants in the United States with a good safety profile.16–21 In 2009, 4 doses of the ALVAC-HIV vCP1521 vaccine plus 2 booster doses of a recombinant glycoprotein 120 subunit vaccine (AIDSVAX B/E) showed a preventive efficacy of 31.2% in a modified intent to treat analysis among Thai adult vaccine recipients.22 This study builds on the previous experience of several clinical trials evaluating different candidate HIV vaccines in infants, mostly conducted in the United States.16,23–25 These include studies of 2 different ALVAC-HIV vaccine products and 3 recombinant envelope subunit vaccines using a variety of doses, immunization schedules, and combinations of products. Pediatric AIDS Clinical Trials Group 230 evaluated the safety and immunogenicity of the Chiron rgp120 (SF-2 strain) with MF59 adjuvant or the VaxGen monovalent rgp120 (MNstrain) adsorbed into alum.24 Pediatric AIDS Clinical Trials Group 326 studied the safety and immunogenicity of 2 different canarypox vectors (ALVAC-HIV vCP205 and vCP1452) with and without a boost with a combination of 2 recombinant gp120 subunit proteins derived from MN and GNE8 strains (VaxGen AIDSVAX B/B).23 These studies also demonstrated the feasibility of conducting HIV vaccine trials in infants, vaccine safety, and the ability of the neonatal immune system to respond to vaccination similar to responses seen in adults in non-African populations.
The HIV Prevention Trials Network (HPTN) 027 Trial evaluated the safety, tolerance, and immunogenicity of the same ALVAC-HIV vCP1521 product alone in HIV-exposed Ugandan infants. The feasibility and safety of conducting this first infant HIV vaccine trial in a resource-limited setting are reported.
HPTN 027 was a phase 1 randomized, double-blind, placebo-controlled trial to evaluate the safety and immunogenicity of ALVAC-HIV vCP1521 among infants born to HIV type 1 (HIV-1)–infected Ugandan women. Eligible infants were enrolled and randomized at birth and followed for 2 years. The study was conducted by the US National Institutes of Health–funded Makerere University—Johns Hopkins University Research Collaboration clinical trial site, located at Mulago National Referral Hospital in Kampala, Uganda. Study data were managed and analyzed by the Statistical Center for HIV/AIDS Research & Prevention in Seattle, WA.
The study was approved by the National HIV/AIDS Research Committee in Uganda, the Johns Hopkins Medicine Institutional Review Board, Uganda National Council of Science and Technology, and the Makerere—Johns Hopkins Institutional Biosafety Committee and as per Helsinski declaration of 1975 as revised in 2000. Import approval for the study products was provided by the Uganda National Drug Authority. This study is registered with http://clinicaltrials.gov/, identifier NCT00098163.
Preparation of the Research Site and Community
This was the first study testing an HIV vaccine among HIV-exposed infants in Africa. A 12-member Community Advisory Board comprised of religious leaders, a former research participant, political leaders, and youth leaders was formed and educated about HIV vaccine trials and HIV infection. The Community Advisory Board assisted the study team with development of participant education materials, consent forms, and community outreach activities. The study team held interactive sensitization workshops regarding HIV vaccines, which included disposing of fears and myths about vaccine trials. Workshops were held with the Ministry of Health, local scientists, media, other health policy personnel, and hospital health care workers.
Study infants were born to HIV-infected pregnant Ugandan women who provided written consent for screening in their third trimester. Inclusion criteria included the following: age ≥18 years, confirmed HIV infection, CD4 cell count >500 cells per microliter, willingness to be visited at home, and intent to deliver at Mulago Hospital. Women who met these criteria received information and counseling about the requirements for infant participation and those willing to continue provided a second written informed consent for screening and enrollment of their infant.
After delivery, maternal consent for the infant's participation in the study was verbally re-confirmed, and the infant's eligibility for enrollment was assessed. Infant inclusion criteria included the following: age ≤3 days, birth weight ≥2000 g, hemoglobin ≥12.0 g/dL, platelet count ≥100,000 cells per cubic millimeter, absolute neutrophil count ≥1500 cells per cubic millimeter, creatinine ≤1.3 mg/dL, and alanine aminotransferase ≤171 U/L. Infants with known HIV infection before vaccination or serious illnesses or medical conditions that would interfere with ability to complete study requirements were excluded. A specimen for HIV testing had to be drawn, but infants could be enrolled and vaccinated before the results were not yet available.
All study women and infants received the Mulago Hospital standard PMTCT regimens (single-dose nevirapine and/or azidothymidine) according to Uganda Ministry of Health guidelines, which were consistent with WHO 2006 recommendations. Children received routine immunization with BCG and polio at birth; polio and tetravalent diphtheria, polio, hepatitis B, and haemophilus influenzae type B at 6, 10, and 14 weeks; and measles at 26 and 52 weeks.
Randomization and Masking
Enrolled infants were randomized 4:1 to ALVAC vaccine or placebo using block randomization. Both the vaccine and placebo products were packaged in identical, sequentially numbered individual kits, each of which contained a complete set of doses required for a single infant. After confirmation of eligibility, the next sequentially numbered kit was assigned to an infant and associated with his/her unique study identification number. Assignment of the kit was the effective point of randomization. Study clinicians and participants were blinded to the identity of study product. To avoid unblinding because of potential differences in appearance between the vaccine and placebo products, the syringe had an overlay and the pharmacists and nurses responsible for dispensing and administering the study product did not participate in clinical assessment of participants.
Study Products and Administration
The ALVAC-HIV vCP1521 is a preparation of a live attenuated recombinant canarypox virus expressing gene products from the HIV-1 clade E env, clade B gag, and clade B protease coding sequences. ALVAC-HIV vCP1521 was formulated as a sterile, lyophilized product in single-dose vials that was reconstituted with sterile sodium chloride solution (0.4%). Each vial contained ≥106.0CCID50/mL of ALVAC-HIV vCP1521. Sodium chloride injection USP, 0.9%, was used as the placebo control. One milliliter of study product was administered intramuscularly into the right thigh muscle.
The study products were administered at birth (0–3 days after birth) and at weeks 4, 8, and 12. Each infant was observed in the clinic for at least 1 hour after vaccination and then examined in the clinic or at home for the next 2 days for assessment of local and systemic reactogenicity events (REs). REs were graded according to the study's Supplemental Toxicity Table for Grading Reactogenicity occurring within 7 days of study vaccination, specific to infant reactogenicities.26 Vaccination was withheld in infants with fever >38°C, abnormal vital signs or clinical symptoms that could mask assessment of vaccine reaction, unresolved grade 3 adverse events (AEs), serious intercurrent infection, or a positive HIV DNA polymerase chain reaction (PCR) test. Vaccination was permanently discontinued in infants with any grade 4 AE, known or suspected disease of the immune system, active tuberculosis, measles, severe malnutrition, immunosuppressive therapy, confirmed HIV infection, and confirmed CD4 cell percent <25. Vaccinations had to be administered within 7 days of the scheduled date; otherwise, subsequent vaccinations were permanently discontinued. The number of study vaccinations received did not affect a child's 24-month follow-up period.
Schedule of Evaluations
Infants were evaluated in the study clinic every 2 weeks from birth to 14 weeks of age, at 5 and 6 months, and then every 3 months until 24 months of age. Specimens were obtained for laboratory safety evaluation, HIV status determination, or immunologic evaluation at weeks 0, 2, 6, 10, and 14 and months 6, 12, 18, and 24. Antibody titers to routine immunizations were measured at 6 months (polio, tetanus, hepatitis B, and haemophilus influenzae type B) and measles at 18 months.
Safety Monitoring and Routine Antibody Tests
At each study visit, children were evaluated for the presence of any clinical or laboratory AEs, the severity of which were graded using the National Institutes of Health, Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, dated December 2004.27 The study database included information on all AEs through the first 6 months of life; thereafter, only serious adverse event (SAEs) data were collected. Safety monitoring was multitiered. The first-level site review was performed by the site clinicians and principal investigator. A physician reviewed and reported all serious and expedited AEs. All AEs ≥grade 3 were reviewed in real time by a Protocol Chair. Second-tier review of AEs was conducted by safety specialists at the data center, and tertiary reviews were conducted by a Protocol Safety Review Team and an external study monitoring committee. Protocol-specified safety pauses were triggered by a potentially related death or multiple similar grade 3 or higher AE and required review by the Protocol Safety Review Team before continuing randomization or vaccination.
Methods for measuring immune response to routine vaccination included the following: poliovirus antibody microneutralization test with neutralizing serum antibody titers (immunity titer ≥ 1:8), quantitative hepatitis B surface antibody by chemiluminescence immunoassay (immunity ≥ 10 mIU), and enzyme-linked immunosorbant assays for tetanus antitoxoid antibodies (immunity ≥ 0.50 IU/mL), HIB antibodies (immunity ≥ 1.0 mcg/mL), and measles antibody (categorized as negative, positive, or equivocal).
Definition of Infant HIV Infection Status
Infant HIV infection status was determined using the Roche AMPLICOR HIV-1 Version 1.5 DNA PCR assay (Roche Diagnostics Corporation, IN) with quality monitored through laboratory participation in the DAIDS Virology Quality Assurance Program. HIV DNA testing was performed at birth, weeks 2, 6, 10, and 14, and months 6, 12, 18, and 24. Infants were considered HIV infected if they had 2 positive PCR results on 2 separate specimens. Rapid HIV testing, followed by confirmatory Western blot testing when necessary, was performed at 18 and 24 months. In the case of a positive antibody test in the absence of documented HIV infection by HIV PCR, antibody testing would be repeated every 6 months until resolution.
The study target required 50 fully evaluable infants to receive all 4 scheduled study vaccinations and be HIV uninfected at the 12-month time point. An additional infant was randomized for each infant who was not fully evaluable, up to the prior accepted 10 additional infants. This sample size provides 80% power to detect a ≥57% difference in toxicity rates between the treatment and placebo groups, with alpha level at 0.05. The primary safety end point was assessed by comparing overall rates of grade 3 or higher AE attributable to receipt of the study product between the vaccine and placebo groups. The rates of all AEs, including those considered mild and moderate, were also compared. Given the small sample size, Fisher exact test and Wilcoxon rank sum test were used for the comparisons. Frequencies of severe AEs and REs were tabulated. Time to cessation of breastfeeding was analyzed by Kaplan–Meier survival analysis. Both arms produced a known antibody threshold consistent with clinical protection as illustrated by the vertical lines in Figure 2.
The strict eligibility criteria and intensive study schedule of evaluations required for this phase 1 safety trial in infants led to a large number of women being assessed for eligibility throughout the multiple stage enrollment process (Fig. 1). Among the 222 women who provided informed consent for screening, over half were excluded because of having CD4 cell counts ≤500 cells per microliter.
Sixty infants were enrolled in the study and randomized (48 vaccine and 12 placebo) from October 2006 to May 2007 (Fig. 1). Characteristics of mothers and infants were similar in both groups except that mothers in the vaccine group were younger (25 vs. 31 years) (Table 1). The median duration of breastfeeding was 155 days for infants in the placebo arm (95% confidence interval: 0 to 638) vs. 181 days (95% confidence interval: 154 to 257) for infants in the vaccine arm. One infant was withdrawn from the study before the 2-week visit by the mother for social reasons. All other infants attended all the scheduled study visits, and all protocol-related evaluations were conducted, including HIV testing by DNA PCR. Retention at 3 years of age was 98%.
All 60 infants received at least 1 study vaccination. Forty-seven infants (38 vaccine and 9 placebo) received all 4 study vaccinations and were HIV uninfected at the 12-month visit. Thirteen infants were discontinued from receiving the full vaccine schedule because of the CD4 cell count <25% (2 vaccine and 1 placebo), grade 4 events (4 vaccine), death (1 vaccine), withdrawal of informed consent (1 placebo), and HIV infection (3 vaccine and 1 placebo). Three of the 4 infants diagnosed with HIV infection during the study received a single study vaccination before the availability of the DNA PCR test results that indicated that they were HIV infected at birth. One infant with a negative PCR at birth received one ALVAC vaccination and then was found to be HIV infected at 2 weeks of age.
Most REs were mild, and there were no significant differences between the 2 study arms (Table 2). There were no severe REs, and all events resolved spontaneously within 3 days after vaccination.
No safety pauses were required during the trial. Fifty-nine infants experienced a total of 711 AEs during the study follow-up. Ninety-eight percent of AEs were assessed as not related (74%) or probably not related (24%) to study product. Most AEs (90%) were of mild (62%) or moderate (28%) severity and included mainly infections or abnormal laboratory results.
There was one grade 3 asymptomatic elevated liver enzyme that was possibly related to receipt of the vaccine. The most common laboratory abnormalities included decreased neutrophil count, decreased hemoglobin, and increased serum bilirubin levels in asymptomatic infants. The frequency of these events was comparable in the 2 study arms (data not shown).
Six infants (50%) in the placebo arm and 27 infants (56%) in the vaccine arm experienced at least 1 serious AE (P = 0.75) (Table 3). There were a total of 58 SAEs that occurred in these infants; 51 in the vaccine arm and 7 in the placebo arm. The majority of SAEs were common childhood illnesses in developing countries. There were 3 infant deaths, all judged to be unrelated to study products. The causes of death were as follows: death at home from pneumonia-like symptoms as reported by the infant's caretaker (vaccine arm), cor pulmonale secondary to congenital heart disease complicated by pneumonia (vaccine arm), and gastroenteritis with electrolyte imbalance (placebo arm).
There were no clinically significant differences found in antibody titers to routine immunizations between the vaccine and placebo recipients for polio, tetanus, hepatitis B, or haemophilus influenzae B at 6 months (Fig. 2) or measles at 18 months.
HPTN 027 is the first HIV vaccine trial conducted in HIV-exposed infants in Africa. This phase 1 clinical trial demonstrated that high-quality HIV vaccine trials in infants are possible in settings with limited resources, where the majority of the world's perinatal HIV transmission occurs. We also found similar and high antibody responses to routine childhood vaccines among infants given the ALVAC-HIV vCP1521 vaccine compared with placebo. Although the numbers are small, this provides some reassurance that the HIV vaccine did not interfere with immune responses to routine immunizations.
The results of the HIV vaccine trial in Thailand that used the same ALVAC-HIV vCP1521 vaccine with the addition of AIDSVAX B/E boosting suggest that vaccination against acquisition of HIV is possible.22 These and other studies in infants must remain high on the HIV vaccine research agenda for both the unique opportunity that studies of MTCT provide and the critical need for an effective vaccine in this population.15,28
HIV-infected Ugandan women were willing to enroll their infants in an HIV vaccine trial for 2 years, despite the intensive follow-up required. The study achieved a high level of participant retention and visit adherence. Proactive, intensive, and ongoing HIV vaccine and study education were provided to eligible and enrolled participants through a multistage informed consent process and throughout the study period. Large numbers of HIV-infected women were assessed for eligibility compared with the small number of infants enrolled in the study. However, many of the exclusion criteria, particularly women with CD4 cell counts <500 cells per microliter and the intensive follow-up required for a safety study, would not be necessary for future large efficacy studies.
The ALVAC-HIV vCP1521 vaccine was safe and well tolerated in HIV-exposed infants when given monthly vaccinations in the first 3 months of life. Most reactions to the vaccine were mild to moderate and were consistent with the findings of previous studies of similar ALVAC products in infants and adults16–21 and those seen with other immunizations. The majority of SAEs and laboratory abnormalities were consistent with background illnesses common in children and variations in normal laboratory values in African setting rather than those from populations used in the DAIDS AE grading tables.27,29
Although this study was not an efficacy trial, it is intriguing to note that no infants became infected after the peripartum period, despite the absence of ARV use during the postpartum period for prevention of breast milk transmission at the time and a high rate of breastfeeding in the study population. A study done in a similar population found HIV postpartum transmission rates of 3.3% between 6 weeks and 12 months of age in infants born to women with CD4 cell counts ≥350 cells per microliter, whereas in this study, there was no HIV transmission between 2 weeks and 24 months of age.30 However, this may be because of the small study sample size.
Investigations of the immunologic responses to the vaccine are underway and should also provide insight into the generation of the immune responses after vaccination. Follow-up studies with larger numbers of infants will allow evaluation of vaccine efficacy in this population and collection of additional specimens to evaluate any potential correlates of protection that may be found as scientists investigate immunologic responses in the adult study in Thailand. This phase 1 study of the ALVAC-HIV vCP1521 in infants was planned as the first step in evaluating the safety of the ALVAC product in African infants. This coupled with the high levels of transplacentally acquired maternal HIV antibodies present in these infants born to HIV-infected mothers lead to the study of ALVAC alone in this trial. The expectation was that if this trial were successful, subsequent trials would be conducted with the same or next generation ALVAC with or without a protein boost depending on the outcome of the Thai trial.
There is a significant public health need for an HIV vaccine to protect infants from infection during breastfeeding. Even with the current WHO recommendations for ARV use for PMTCT during pregnancy and breastfeeding, the challenges of sustainability and implementation of increasingly more complex ARV prophylactic regimens for long periods of time postpartum will likely result in ongoing MTCT among breastfed infants living in resource-limited settings. This includes transmission to HIV-exposed infants whose mothers are not identified by PMTCT programs, acquire HIV infection during late pregnancy/breastfeeding, are nonadherent to ARV for the duration of breastfeeding, or are lost to follow-up after delivery.15,31,32 Adding an effective HIV vaccine to the routine childhood immunizations given to all infants would be a simple and cost-effective strategy to reach the global health goal of virtual elimination of HIV infection in children.
This study would not have been possible without the willingness and commitment of Ugandan women to contribute to the search for an HIV vaccine. The authors thank the mothers and families of study participants who volunteered for this trial. In addition, appreciation is given to the Makerere University—Johns Hopkins University Research Collaboration HPTN 027 study team for their dedication to the care and follow-up of study participants, the staff at Makerere University—Johns Hopkins University and the Joint Clinical Research Center, Sanofi Pasteur, Statistical Center for HIV/AIDS Research & Prevention, and FHI360. The authors would like to convey their special thanks to Drs Samuel Adeniyi-Jones, Jean Louis Excler, Jack Moye, and Clemensia Nakabiito for their support for this study and in memory of Dr Mary Lou Clements and Prof. Francis Mmiro, the initial protocol immunologist of the study when first conceptualized and site principal investigator, respectively.
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