Important note: Information in this article was accurate in October 2001. The state of the art may have changed since the publication date. IAVI Report - October - November 2001
Emily Bass
Pediatrics and vaccinology have long gone hand-in-hand. Children, including young babies, were key participants in trials of polio, BCG and measles vaccines, all of which are now given to infants. But HIV has turned this paradigm on its head. Regulatory, ethical and scientific uncertainties have kept studies of HIV vaccines in babies largely off the agenda: So far there have been only two such trials, both in North America, while efforts to launch a third one in Uganda have been years in the making (see IAVI Report, July-Sep. 2001).
Yet every year, 500,000 babies--most in sub-Saharan Africa--become infected with HIV, and the explosive infection rates among young women in much of the developing world mean that these numbers will continue to grow. While wider use of antiretroviral drugs such as nevirapine can help reduce transmission at birth, these gains will be largely offset by infections occurring afterwards via breastfeeding, which remains common among HIV-positive mothers in the developing world for a variety of health and cultural reasons.
On 11-13 October 2001, 21 scientists met in Dedham, Massachusetts to assess the state of the pediatric AIDS vaccine field and look for ways to accelerate progress. Hosted by the Elizabeth Glaser Pediatric AIDS Foundation, the interdisciplinary gathering of pediatricians, vaccinologists, virologists and primate researchers found a shared goal: the need to move pediatric vaccines forward with speed. They also found--perhaps surprisingly--some reasons for optimism amid the grim statistics: Even in the first months of life, the neonatal immune system appears to be capable of robust cellular immune responses to at least some viral pathogens and vaccines.
The meeting also brought striking news from the monkey model system. New data from Marta Marthas' lab at the University of California (Davis) show that a canarypox-based SIV vaccine appears to protect infant monkeys against low-dose oral challenges of pathogenic virus--the first real evidence that a vaccine might protect newborns against repeated exposure to HIV in breast milk.
Members of the group also stressed that some vaccines may be more potent in children than in adults. The varicella vaccine, for example, induces only weak immune responses in adults, who require two doses for protection, while infants are protected after only single one. "If we had done those trials only in adults, we would have said it was not a good vaccine," said participant Ann Arvin, a pediatrician and vaccine researcher at Stanford University.
These leads solidified the consensus that HIV vaccine trials in infants should not always wait until extensive testing in adults is complete. With the tremendous need, and a growing number of vaccine candidates poised to enter the clinical development pipeline, "we need to make these trials as concurrent as possible," said Katharine Luzuriaga, a pediatrician and HIV researcher at the University of Massachusetts. "It is 100% obvious and imperative" that trials should be done in both populations," said Arvin.
The meeting started with discussions acknowledging important scientific gaps. Relatively little is known about how, and how well, the neonatal immune system can respond even to common childhood pathogens or vaccines. Despite a new generation of T-cell assays that can quantitate cellular responses precisely (see IAVI Report, Dec. 2000-Jan. 2001) there has been little interest, or funding, for going back to look at how any licensed vaccines actually work. As a result, said John Sullivan of the University of Massachusetts, "we know more about HIV-specific cell-mediated immunity in infants than we do about any other disease." One challenge in devising a vaccine strategy for infants of HIV-positive women is that exposure and infection can occur in the womb. Yet despite this in utero exposure to viral proteins and particles, the majority of these babies are born HIV-negative, for reasons that are not well-understood (see IAVI Report, July-Sep. 2001, p.4). Glenda Gray (Chris Hani Baragwanath Hospital, Johannesburg) discussed some new clues, presenting data from a recent paper showing that the presence of Env-specific T-helper responses in cord blood correlates with protection from intrapartum and breastfeeding infection (AIDS 2001 Jan 5;15(1):1-9 ). Other researchers, including Sarah Rowland-Jones (Lancet 1993 Apr 3;341(8849):860-1) have also found HIV-specific cellular responses in exposed, uninfected infants.
Another perspective came from Katharine Luzuriaga and John Sullivan, who described a new study of CD8+ CTL responses in 17 HIV-infected infants before and after the initiation of HAART (J Immunol 2001 Dec 15;167(12):7134-40). Prior to HAART, only 2/13 infants had detectable HIV-specific responses; in contrast, three infants co-infected with HIV-1 and CMV had detectable CD8 responses to CMV at all time points (1-23 months), but none to HIV. This could be due to differences in viral presentation in utero. Or, as the researchers suggest, there could be an HIV-specific effect on the CD8+ T-cells needed to fight off infection, or on the immune signals that call them to action.
In addition to virus-related effects, there are inherent limitations due to the immaturity of the neonatal immune system. Luzuriaga and others have shown that infants who start HAART before six months of age and achieve complete viral suppression lose all signs of HIV-specific immune responses, while infants who begin HAART after six months retain these responses. As meeting participant Bruce Walker (Harvard University) pointed out, the loss of these responses in the youngest infants, who are often acutely affected at delivery, contrasts with the finding that many adults treated during acute infection maintain detectable HIV-specific immune responses.
The possibility of an HIV-specific rift in the fabric of early immunity poses another set of challenges for vaccine developers. Not only will a pediatric HIV vaccine have to overcome possible immune deficiencies from viral exposure, it should also elicit protective responses from an immune system in the early stages of development--the sooner the better, since transmission via breast milk seems to be highest in the first six weeks after birth.
For many diseases, babies' early immunity comes from maternal antibodies in breast milk, which has evolved to provide this protection. But these maternal antibodies are generally useless against HIV. Yvonne Bryson (UCLA Medical Center, Los Angeles) reviewed data showing that, in most cases, maternal antibodies to HIV do not neutralize the infant's virus. She also said that infants without neutralizing antibody from their mothers also lack their own HIV-specific responses and progress rapidly to AIDS.
Yet when maternal antibody does neutralize the infant's virus, Bryson added, this correlates with lower viral load in the baby's blood. These findings echo earlier results from macaques (Ruprecht, Transfus Clin Biol 2001 Aug;8(4):350-8, and Mascola, J Infect Dis 1998 May;177(5):1230-46) showing that passive transfer of certain monoclonal antibody cocktails protects some neonates against mucosal challenge.
Nonetheless, it is highly unlikely that vaccines alone could protect newborns right from birth. So they will most likely be tested in combination with another anti-HIV intervention given early on, such as antiretroviral therapy or antibody cocktails, that can protect infants until HIV immune responses kick in. Having laid out the pieces of the puzzle, the participants acknowledged that pediatric HIV infection does not seem to behave like other perinatally transmitted viruses, such as CMV or Hepatitis B. As Luzuriaga showed, CMV induces strong immune responses in very young infants. Infection of newborns with hepatitis B (HBV) happens almost exclusively during labor; treatment with antibody (HbIg) plus hepatitis B vaccine effectively prevents chronic infection in about 85% of these infants.
The evidence for HIV-specific T-helper responses in uninfected infants is also confounding. "It has not been reported for any other pathogen that the infant is born with immunity and yet has no evidence of infection at some point in postnatal life," says Ann Arvin. The lack of precedent is one reason Arvin and others are skeptical about the reported association with protection.
Without clear parallels in other models, researchers stressed the need for HIV studies on pairs of maternal and infant cord blood samples. That could help settle key questions, such as whether the CD4 T-cells detected in the South African study are made by mother or baby. Also needed are neonatal cohorts for examining why some infants respond better to antiretroviral treatment than others, and what factors influence infants' HIV vulnerability and protection. "Without such studies, we are never going to know the numerator or the denominator for how many kids make immune responses and under what conditions," said Gray.
What are the models? Is HIV following different rules? Or have we failed to understand the rules as they are? Bruce Walker posed this question as the meeting segued into a discussion of other models. However imperfect such comparisons may be, studies of proven vaccines may help reveal what types of immune responses are generated after birth, and how quickly.
Ann Arvin and her colleague Hayley Gans (Stanford University) reviewed their studies of measles vaccines, providing an in-depth picture of humoral, cellular and cytokine responses in 248 infants immunized at six (n=93), nine (n=77) and 12 (n=78) months. In their studies, younger babies received live measles or mumps vaccine at six and nine months of age, followed by live-attenuated measles-mumps-rubella (MMR-II) vaccine at 12 months; babies enrolled at 12-months or older received a single dose of MMR-II.
All infants showed robust measles-specific T-helper responses, as measured by T-cell proliferation and interferon-gamma production assays 12 weeks after vaccination. That applied equally to babies with maternal antibody, contradicting the dogma that maternal antibody interferes with vaccine response--perhaps by "soaking up" vaccine antigen.
However, the findings differed for antibody responses. Using a level of 120 µIU (milli-international units) of neutralizing antibody--the threshold previously correlated with protection against measles--Arvin and Gans found that only 36% of the 6-month old infants showed this response, compared to 100% of 9- and 12-month olds. No differences were seen between 6-month old children of unvaccinated versus measles-vaccinated mothers (who lack or have low levels of measles antibody), again contradicting the idea that maternal antibody invariably reduces immune responses in the babies.
Perhaps the most important lesson from the measles model is that early cellular defenses are readily induced, and may provide protection before antibodies appear. "You will find so many people who say that antibodies alone protect from measles and varicella," noted Arvin. "I feel it is a gap in our thinking, because the rest of the [immune] response was never measured."
Arvin was among the many speakers who emphasized that there is probably more than one component of neonatal protection, and that the ingredients of natural protection may differ from those induced by vaccines. In her view, even vaccines that induce only some components--for example, cellular but not humoral responses--are still worthy candidates. "It seems like that child would be way better off than one who hasn't been immunized," she said.
Marta Marthas (California Primate Research Center, University of California at Davis) showed preliminary data from an HIV vaccine study that looked for protective responses in neonatal macaques fed SIV orally. Eight newborn macaques were immunized at 0, 2 and 3 weeks of age) with a canarypox vaccine vector (ALVAC) containing gag, pol and env, and nine newborns with an MVA vector containing gag and pol (0, 3 weeks). At week four, all immunized and control animals were given repeated low-dose oral challenges with SIVmac251 (three times daily for five days). By 12 weeks after challenge, 7 of the 9 MVA-immunized animals were infected (peak viremia 106-107), along with 7/8 controls (with peaks between 107 and 108)--but only 2/8 of the ALVAC group.
Differences in immunization schedules and HIV antigens in the two vaccines prevent a straightforward comparison of the approaches. But if the canarypox data hold up with larger numbers of animals, they bode well for prospects that a vaccine can induce protection in breastfeeding infants. And they may bolster arguments for the Phase III canarypox trials under consideration by a US/Thailand Army collaboration and by NIAID's HIV Vaccine Trials Network (HVTN) (see articles).
They also suggest that different challenge routes and doses can lead to different results: Genoveffa Franchini saw no protection in macaques immunized with the same stock of the vaccine, given as a single, high-dose rectal challenge (J Virol 2002 Jan;76(1):292-302).
Currently, there are only a handful of pediatric vaccine trials in the cards/ But there are signs that times are changing: PACTG 1033 is planned as a Phase I therapeutic vaccine study that will evaluate safety and immune responses of infected children on HAART to two new vaccines--one based on MVA and the other on fowlpox (both newly made by Therion Biologics) expressing genes from early infant HIV isolates. These vaccines have not yet been tested in adults, and are also slated for an adult Phase I HVTN-sponsored trial, which is still being designed.
Despite these glimmers of hope, expanding the number of pediatric trials may not be easy, said James McNamara, chief of the Treatment Research Program at NIAID's Division of AIDS (DAIDS), who noted that history seems to be repeating itself. "We're having the same conversation we had ten years ago about therapeutics," he said. "There is the same reluctance to put these experimental agents into kids."
Yet there is also the possibility that an effective HIV vaccine could be found faster for babies than for adults. Commenting on the outcome of the therapeutic studies, says Luzuriaga, "In the early nineties, people assumed that the antiretroviral agents would have to go to adults before children. We worked hard to change that, and it turned out that children [get better results] on antiretrovirals than many adults. I think the same will be true for vaccines."
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©2001. The IAVI Report.
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