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JAIDS Journal of Acquired Immune Deficiency Syndromes:
Epidemiology and Social Science

Immunoprophylaxis to Prevent Mother-to-Child Transmission of HIV-1

Safrit, Jeffrey T. PhD*; Ruprecht, Ruth MD, PhD†; Ferrantelli, Flavia PhD†; Xu, Weidong PhD†; Kitabwalla, Moiz PhD†; Van Rompay, Koen DVM, PhD‡; Marthas, Marta PhD‡; Haigwood, Nancy PhD§; Mascola, John R. MD¶; Luzuriaga, Katherine MD**; Jones, Samuel Adeniyi MD, PhD††; Mathieson, Bonnie J. PhD‡‡; Newell, Marie-Louise MB, PhD§§; Ghent IAS Working Group on HIV in Women Children

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From *Elizabeth Glaser Pediatric AIDS Foundation, David Geffen School of Medicine, University of California, Los Angeles; †Dana Farber Cancer Institute and Harvard Medical School, Boston, MA; ‡California National Primate Research Center, University of California, Davis; §Seattle Biomedical Research Institute, WA; ¶Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD; **University of Massachusetts Medical School, Worcester, MA; ††Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, MD; ‡‡Office of AIDS Research, National Institutes of Health, Department of Health and Human Services, Bethesda, MD; §§Institute of Child Health, University College London, London, UK.

Received for publication June 5, 2003; accepted October 31, 2003

Federal Government disclaimer: The information, opinions, data, and statements contained herein are not necessarily those of the US Government, the Department of Health and Human Services (DHHS), National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID), or Office of AIDS Research (OAR) and should not be interpreted, acted upon, or represented as such.

Correspondence: Marie-Louise Newell, Centre for Paediatric Epidemiology and Biostatistics, Institute of Child Health, University College London, UK (e-mail: m.newell@ich.ucl.ac.uk).

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Abstract

Antiretroviral therapy can profoundly reduce the risk of mother-to-child transmission (MTCT) of HIV, but the drugs have a relatively short half-life and should thus be administered throughout breast-feeding to optimally prevent postnatal infection of the infant. The potential toxicities and the development of resistance may limit the long-term efficacy of antiretroviral prophylaxis, and a safe and effective active/passive immunoprophylaxis regimen, begun at birth, and potentially overlapping with interpartum or neonatal chemoprophylaxis, would pose an attractive alternative. This review draws on data presented at the Ghent Workshop on prevention of breast milk transmission and on selected issues from a workshop specifically relating to immunoprophylaxis held in Seattle in October 2002. This purpose of this review is to address the scientific rationale for the development of passive (antibody) and active (vaccine) immunization strategies for prevention of MTCT. Data regarding currently or imminently available passive and active immunoprophylaxis products are reviewed for their potential use in neonatal trials within the coming 1–2 years.

The transmission of HIV-1 from an infected woman to her infant is the predominant mode of pediatric HIV-1 infection. The increasing incidence and prevalence of HIV-1 in young women of childbearing age and the need to continue breast-feeding in many resource-poor settings to reduce infant mortality have resulted in an urgent need for effective strategies to prevent mother-to-child transmission (MTCT) of HIV-1 infection. Globally, the World Health Organization has estimated 5 million people became infected in 2002, 800,000 of them children; almost all were infected through MTCT. The majority of MTCT worldwide occurs at delivery or after birth through breast-feeding. Antiretroviral therapy for pregnant women and their infants can profoundly reduce the risk of MTCT (see Gaillard et al., p. 178 in this issue). However, antiretroviral medications have a relatively short half-life and should thus be administered throughout the course of breast-feeding to optimally prevent infection in the infant. Additionally, the potential toxicities and the development of resistance are likely to limit the long-term efficacy of antiretroviral prophylaxis against MTCT of HIV-1. A safe and effective active/passive immunoprophylaxis regimen, begun at birth, and potentially overlapping with interpartum or neonatal chemoprophylaxis, would therefore pose a more attractive strategy and might also provide the basis for lifetime protection against HIV-1 infection. In fact, empirical immunoprophylaxis studies designed to prevent breast-feeding transmission may allow accelerated efficacy testing of vaccine candidates and antibody products. This is primarily due to the large numbers of infants born at risk and the high rate of breast-feeding transmission within the first 6 months of life. Such studies could reach definitive endpoints at 18 months in populations of infants who were born to mothers with known HIV infection and who were receiving perinatal antiretroviral interventions.

This review draws on data presented at the Ghent Workshop on prevention of breast milk transmission as well as selected issues from a workshop entitled “Immunoprophylaxis for HIV-1 in pediatrics: moving concepts to reality on vaccines and passive immunity” held in Seattle during October 2002. The latter workshop was co-sponsored by the Division of AIDS, National Institute of Allergy and Infectious Diseases and Office of AIDS Research, National Institutes of Health, DHHS, and the Elizabeth Glaser Pediatric AIDS Foundation. This purpose of this review is to assemble the available data from animal models and human trials to address the scientific rationale for the development of passive (antibody) and active (vaccine) immunization strategies for prevention of MTCT. Data regarding currently or imminently available passive and active immunoprophylaxis products are reviewed for their potential use in neonatal trials within the coming 1–2 years.

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PASSIVE HIV-1 PREVENTION STRATEGIES: MONOCLONAL/POLYCLONAL ANTIBODIES

Antibodies are clearly involved in protection against numerous infectious diseases. Childhood vaccines where antibodies are the correlates of protection such as hepatitis B, Haemophilus influenzae B, diphtheria, and tetanus are certainly some of the most successful vaccines. 1 However, babies of HIV-infected women often become infected despite the presence of passively transferred maternal anti-HIV antibodies. While the reasons for failure of maternal antibodies to protect from infection may be complex and incompletely understood, viral escape from neutralizing antibodies is clearly a potential mechanism and has been found to account for shifting viral diversity over time in infected adults 2,3 and in children with different rates of disease progression. 4 Unfortunately, HIV is a more complex pathogen than many of those for which we have successful vaccines. In fact, the role of antibodies in preventing MTCT, whether simple binding to or neutralization of virus or engaging antibody-dependent cell-mediated cytotoxicity (ADCC) of infected cells, has been a subject of controversy. Early data from Rossi et al. 5 and Scarlatti et al. 6,7 showed a positive correlation with the presence of antibodies recognizing HIV gp120 epitopes, including the V3 loop, and lower transmission from mother to child. However, more recent data show no such correlation for MTCT of clade C HIV-1 in Zimbabwe. 8 Others suggest that an array of antibodies to envelope epitopes, including those in gp41, provided benefit to infants. 9,10 In addition, early studies by Broliden et al. 11 suggested that maternal antibodies able to provide antibody-dependent cell-mediated cytotoxicity were correlated with better survival of HIV-infected infants, although there was no evidence that these antibodies prevented MTCT, consistent with their mode of action against infected cells.

Maternal antibodies, either capable of traversing the placenta or present in breast milk, are important for protection of neonates from many bacterial and viral pathogens including those mentioned here. 12 It has been difficult, if not impossible, however, to raise antibodies that can neutralize a wide array of primary HIV isolates with candidate vaccine approaches tested to date. However, several unique monoclonal antibodies that can neutralize many isolates of HIV have been derived from HIV-infected humans. It is mainly these potent examples of anti-HIV-1 monoclonal antibodies that have given potential passive immunoprophylaxis protocols new life, and the successful experiments in animal models, reviewed here, have provided strong supporting data that passive administration of antibodies can prevent HIV infection.

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Animal Models of MTCT and Protection by Antibody Therapy

Neonatal passive immunization experiments have taken 2 approaches in the attempt to interrupt virus transmission from mother to child or to prevent infection via other routes. Both approaches rely on anti–simian immunodeficiency virus (SIV) or HIV antibodies. Based on the accepted use of gamma globulin and virus-specific immune globulin to prevent certain infection in humans, antiviral immune serum or purified immunoglobulins pooled from virus-infected macaques or humans known as SIVIG or HIVIG, respectively, have been used in both animal and human trials. More recently, anti-HIV monoclonal antibodies alone or in combination have been used to prevent infection with chimeric SIV/HIV in neonatal and juvenile macaques.

Experiments by Van Rompay et al. 13 were among the first to use SIV hyperimmune serum to attempt to protect neonates from oral inoculation with SIV. In the protocol, neonatal macaques were given SIV hyperimmune serum before or after inoculation with live SIV via the oral route. Six animals received a dose of the serum by subcutaneous injection at birth. Four of these animals received additional subcutaneous doses at days 7 and 14. All 6 animals were inoculated orally with 1 dose of uncloned SIVmac251 at day 2 after birth and all 6 were protected from infection. However, if the serum was given 3 weeks following SIV inoculation, there was no effect on the infection or normal disease course and all the infants developed simian AIDS within 11–13 weeks. This time frame of progression to disease was comparable to controls that received no serum. In addition, and not surprisingly, the protection conferred by the passive immunoprophylaxis in the original 6 protected animals was not long lived as all 6 became infected when rechallenged with virus at 8–9 months of age, when the passively transferred antibodies were no longer detectable. 13 The macaques therefore did not generate an anamnestic immune response to the original inoculation, probably due to the efficient clearance of the virus by the antibody products.

Mascola et al. 14 have used simian HIV (SHIV) infection of macaques as a model to investigate the protective requirements of passive antibodies, both HIVIG and monoclonal combinations. In these experiments, juvenile macaques received intravenous infusions of HIVIG or monoclonal antibodies 2F5 and 2G12 and were then challenged 24 hours later with SHIV 89.6P by either the intravenous or vaginal route. Regardless of the route of challenge, complete protection against SHIV infection could be achieved. The more potent triple combination of monoclonal antibodies and HIVIG provided the best in vivo protection, but even a single monoclonal antibody could provide partial protection against SHIV-associated disease. Vaginally challenged animals were more readily protected by antibody infusion than intravenously challenged animals and even those infected showed lower plasma RNA levels than after intravenous challenge. 14

Experiments from the laboratory of Ruth Ruprecht have demonstrated the success of passive transfer of monoclonal antibodies for protection from infection in the neonatal macaque model. Again using a chimeric SHIV to allow evaluation of anti-HIV Env human antibodies in macaques, but now using combinations of up to 4 monoclonal antibodies, sterilizing protection has been seen. In their experiments, Macaca mulatta (rhesus) neonates are given oral, nontraumatic exposure to SHIV within 5 days of birth.

Thus far, a total of 31 newborn rhesus monkeys have been treated with triple or quadruple combinations of human neutralizing monoclonal antibodies (nmAbs) against oral challenge with different SHIV strains. All untreated controls were infected, whereas 22 of 31 treated infants were completely protected (no virus was found at any time). In addition, no neutralization escape mutants were found in an nmAb-treated monkey that became infected 15–18 (Ferrantelli, unpublished results).

The selection criteria for the human nmAbs were stringent. For use in these latter monkey experiments and for ultimate use in humans, the antibodies were chosen based on targeting to conserved epitopes that would have less chance of generating escape mutant viruses. The antibodies had to be relatively potent as single agents, including neutralization of primary HIV isolates. Synergistic interaction with other nmAbs in the combination regimen was critical because it was thought that the monoclonal antibodies used singly would be less effective and could more easily select for virus escape mutants. Finally, the monoclonal antibodies had to be available in sufficient quantities for the experiments to proceed.

The neutralizing anti-HIV antibodies used by Ruprecht and Mascola were isolated from HIV clade B–infected individuals. The antibodies were then expanded as monoclonal antibodies and have been examined for their epitope specificity. Monoclonal antibodies F105 and b12 were found to be specific for the CD4 binding site on gp120 (Fig. 1). Monoclonal antibody 2G12 recognized a complex epitope on gp120 dependent on correct N-linked glycosylation. Monoclonal antibodies 2F5 and 4E10 recognized linear epitopes on gp41, ELDKWA, and NWFDIT, respectively (F105, 19 IgG1b12, 20 2G12, 21 2F5, 22 and 4E10 23).

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Several questions were addressed with the design of the experiments in the juvenile and neonatal monkey models. Can human nmAb combinations protect neonatal rhesus macaques against oral challenge with an acutely pathogenic, chimeric SHIV that encodes the env gene of a primary HIV isolate? Will passive immunization with human nmAb combinations still completely protect neonatal macaques, even when given as postexposure prophylaxis?

The virus used in many of these experiments is one that fits the above criteria. SHIV89.6P contains an envelope gene that was derived from HIV89.6, a primary, dualtropic strain isolated from an AIDS patient inserted into a SIVmac239 backbone. Importantly, the serially passaged SHIV89.6P recombinant virus stock replicates in rhesus macaque peripheral blood mononuclear cells and results in acute pathogenesis and persistent infection in adult and neonatal macaques. Typically, CD4+ T-cell numbers decrease precipitously 2 weeks after inoculation, and most monkeys do not recover and die of AIDS. 24 In fact, because this particular virus uses both CCR5 and CXCR4, unlike most cases of human transmission, protection achieved against SHIV-89.6P could be considered more difficult than against viruses that use single co-receptors for entry. Conversely, others have argued that the rapid decline in CD4 T cells caused by SHIV89.6P is abnormal and that the virus is unusually sensitive to autologous neutralizing antibodies. 24–27 Ultimately, however, because this virus has been used in multiple experiments from different laboratories, comparisons between antibody products may at least be possible.

In a like manner, postexposure prophylaxis protection may be the most difficult to achieve but the most likely scenario and best harbinger of the potential for monoclonal antibodies to be effective agents for the prevention of MTCT. In the experiments by Ferrantelli et al., 18 neonatal macaques were inoculated with SHIV89.6P orally at day 0 (days 1–5 after birth) and treated with a combination of 4 nmAbs (IgG1b12, 2G12, 2F5, and 4E10) intravenously at 1 hour after virus challenge and again 8 days after the virus. The control group was left untreated after virus exposure.

The results from this experiment are encouraging. Two of 4 nmAb-treated animals have showed no signs of virus at any time, while the remaining 2 became infected but had lower peak viremia than controls and have maintained CD4 cell levels. Three of the 4 treated animals were well after >1 year. In contrast, all 4 control animals became infected by SHIV89.6P, lost CD4 cells by 2 weeks after the challenge, and 3 of 4 died of SAIDS within 1.5–6 weeks after the start of the experiment. 18

In recent experiments designed to improve on the artificial nature of the macaque model for MTCT, Haigwood et al. (personal communication) have developed one of a natural virus transmission from mother to infant. The goal of these experiments was to establish a model more representative of human MTCT from in utero through to breast-feeding transmission. Using the macaque model of SHIV infection, pregnant pig-tail macaques were inoculated with 100 monkey infectious doses of SHIV-SF162P3 27 during the 10th–12th weeks of pregnancy. This chimeric virus utilizes a CCR5-using envelope of HIV-1 that is the major transmitting form in human MTCT. After vaginal delivery, the neonates were kept with their mothers for suckling. To date, 2 of 6 infants born to SHIV-infected dams have become infected. In the dams, maternal neutralizing antibody correlated with reduced viral load and nAb was transferred via the placenta to the fetuses. This model will allow the investigation of variables that limit or facilitate MTCT, where the input viral genotype and time of infection are constants. If transmission rates are high enough, it may also be possible to apply what has been learned previously in macaque experiments to this natural transmission model to examine the effects of drugs or nmAb interventions.

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Setting the Stage for Human Efficacy Trials of Passive Immunity

Given the results seen here, is postexposure prophylaxis or passive immunization a valid strategy to prevent MTCT in sub-Saharan Africa, especially breast milk transmission? In order for these monoclonal antibodies to work in a region such as Southern Africa, the antibodies would need to be effective against more than just the clade B HIV strains that they were originally targeting. As a reminder, of the main group M viruses responsible for most HIV infections globally, clade A is predominantly found in Western and Central Africa; clade B in North and South America, Europe, Asia, and the Caribbean; clade C in Southern and Central Africa and India; clade D in Central and Eastern Africa; clade E in Southeast Asia, clade F in South America and Eastern Europe; clade G in Central and Western Africa and Western Europe; and clade H in Central Africa. 28,29 Thus for passive immune protection to work in sub-Saharan Africa, the monoclonal antibodies would need to neutralize multiple isolates from different clades or circulating recombinant forms.

Recent results speak to the issue of the potential for a cocktail of mAbs to provide protection across a wide range of HIV-1 isolates from different clades and circulating recombinant forms. In vitro, the combination of nmAbs IgG1b12, 2G12, 2F5, and 4E10 has a very impressive cross-clade neutralizing profile. Experiments from the groups of Xu et al. 30 and Zwick et al. 31 showed that these mAbs completely neutralized several HIV clade B primary isolates. Potent cross-clade neutralization was also demonstrated for 14 of 20 primary HIV clade C isolates from different parts of the world, including all 4 Chinese isolates, while the remaining 6 isolates were neutralized 97.5–99%. 30 Also, 4 of 4 primary HIV clade A isolates were neutralized >99%32 and 5 of 5 primary HIV clade D isolates were neutralized >99%. 32 Thus, this quadruple nmAb combination has potently neutralized primary HIV isolates of clades A, B, C, and D (Table 1). These results bode well for their use in the areas of the world where they may be the most needed.

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In order for these reagents to move quickly into efficacy trials in humans, the necessary safety studies have already begun. Phase 1 safety testing in humans has been done in HIV-infected adults for 4 of the 5 mAbs that have been the most productive in the macaque experiments. The monoclonal antibodies F105, 33 2F5, and 2G12 34,35 have been previously tested and found to be safe and well tolerated by the patients and the concentrations of antibody achieved in vivo were on the order of those that cause >99% neutralization in vitro. Because of the difficulties inherent in blocking transmission of this virus, an in vivo concentration capable of 99% in vitro neutralization has been suggested as necessary. In addition, the phase 1 trial of the combination of 2G12 and 2F5 revealed transient decreases in viral RNA levels in most treated individuals. 35 Of the other 2 antibodies, 4E10 is currently undergoing phase 1 testing in HIV-infected adults while IgG1b12 has not yet been tested.

These antibodies may have the best chance at blocking MTCT when used immediately after birth and through a limited breast-feeding period. With the success of antiretroviral regimens in reducing MTCT in the developed world, and a prolonged half-life of antibodies to HIV that has been demonstrated in infants, 36 a combination of these modalities may be the necessary and most appropriate way to move forward.

To this end a prospective phase 1 clinical trial of human nmAbs (candidates: 2G12, 2F5, 4E10, or F105) in HIV-exposed, uninfected human neonates is in the planning stages. The results of this trial should provide information about the feasibility of achieving and maintaining high levels of neutralizing antibodies in infants. Ultimately, if babies are protected from HIV infection throughout breast-feeding in a subsequent efficacy trial, the proof of principle for protection by HIV-specific antibodies will have been achieved.

Many questions remain and can be addressed in well-designed trials and analyses. Is passive immunization a promising tool to prevent MTCT of HIV intra- and postpartum? Can passive immunoprophylaxis identify other epitopes that confer complete protection? Can vaccines be designed that preferentially generate neutralizing antibodies against epitopes known to yield complete protection? Can pregnant women be vaccinated with vaccines that generate such antibody responses, and will vaccine-induced nAbs cross the placenta? These are just a few of the questions that both macaque and human trials should begin to answer in the near future. Importantly, epitopes identified through passive immunization may equal correlates of immune protection and thus would be ideal targets for candidate AIDS vaccines.

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Lessons from HIVIG Trials and Further Planned Studies

In addition to the human safety trials noted here, the concept of antibody-based prevention of MTCT has also been tested in the form of pooled and purified immune globulin from asymptomatic HIV-infected individuals. Just as SIV hyperimmune serum was used by Van Rompay et al. in macaque experiments, HIVIG has been used in adult and pediatric trials. As previously mentioned, it is thought that the combination of antiretroviral drugs and antibodies may provide a broader and more prolonged approach against this virus. This concept was tested in the Pediatric AIDS Clinical Trials Group (PACTG) protocol 185. The trial examined whether AZT combined with HIVIG given to the mother during pregnancy and the baby at birth would lower perinatal transmission compared with administration of AZT and control immunoglobulin. 37 The design was built upon the early passive therapy macaque experiments discussed previously and seemed a logical next step. While there was an indication that the HIVIG had a positive effect and reduced HIV-1 transmission in women with either prior AZT use or with CD4 counts < 200, in the groups as a whole, there was no measurable difference overall between the HIVIG and control immune globulin treatments. This was in part due to the unexpected overall low transmission rates in the study, which resulted in the trial being stopped before a sufficiently large sample size could be recruited to exclude any effect. Importantly for international consideration, this study also prohibited breast-feeding. A more recent examination of the safety and effectiveness of a different HIVIG preparation has been conducted in Uganda. So far, the results are similar to the above study. 38 The preparation of HIV hyperimmune globulin (HIVIGLOB, prepared from pooled plasma donations from asymptomatic HIV-infected individuals in Uganda) was shown to be safe in 31 women and 29 of their infants. There was no clear effect of the HIVIGLOB on maternal virologic or immunologic parameters, and the overall transmission rate, while high, was impacted by higher viral loads in the study participants and also by subsequent infection via breast-feeding. There was a trend for lower transmission rate in the mother-infant pairs who received the highest dose of HIVIGLOB but the differences between the study groups were not significant, as expected, due to the small size of this safety study. 38 A phase 3 trial of HIVIGLOB is currently being planned, as part of a study of MTCT through breast-feeding, with nevirapine or other antiretroviral drugs in Uganda (see Galliard et al. in this issue).

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HIV-1 MTCT PREVENTION STRATEGIES: VACCINES AND ANIMAL STUDIES OF VACCINE CANDIDATES

Marthas, Van Rompay and colleagues have recently developed a unique model of neonatal oral transmission of SIV that also more closely mimics breast milk transmission of HIV in human mother-infant pairs. Instead of the above natural suckling method, hand-reared neonates are given multiple low doses of virus orally over an extended period (3 times per day for 5 days). Most control animals challenged in this manner become infected (87.5%, 7/8 to date; Marthas et al, personal communication). Many other previous neonatal macaque studies have used oral challenge with virus but have used large doses of virus to ensure infection of control animals for statistical considerations. Multiple low-dose exposures are most likely to be more comparable to breast milk transmission in humans. However, issues regarding statistical power may need to be addressed if not all control infants become infected.

Several studies by Marthas et al. have investigated the potential of passive and active immunization strategies in newborn and infant macaques. Previous passive immunization studies demonstrated that antiviral IgG, either derived from the maternal circulation (through active immunization of the mother and transplacental transfer of antibodies) or directly administered to the newborn, can protect newborn macaques against oral SIVmac251 infection. 13,39 Strategies using active immunization of the infant have the daunting task that a neonatal vaccine should rapidly induce immunity, even in the presence of maternal antibodies, and should be able to protect against viral transmission through repeated viral exposure during breast-feeding. In a first set of studies, neonatal macaques were vaccinated either with modified vaccinia Ankara (MVA) expressing SIV gag, pol, or env, or the live attenuated SIVmac1A11. When the infant macaques were then challenged with 2 relatively high doses of SIVmac251 orally at 4 weeks of age, all the animals became infected, but the immunized animals controlled virus levels better and had longer disease-free survival than unvaccinated controls. There was no evidence that the presence of maternal antibodies reduced vaccine efficacy of the MVA vaccine. 40 As mentioned previously, these investigators have developed a better model of neonatal oral transmission of SIV that more closely mimics breast milk transmission of HIV. Neonates receive 2 or 3 immunizations with SIV vaccines within the first 3 weeks of life, and at 4 weeks of age, are fed 15 low doses of SIVmac251 over an extended period (3 times per day for 5 days). Using this low-dose SIV challenge model, poxvirus-based vectors (MVA and ALVAC) expressing SIV genes (gag, pol, and env) were found to be partially protective. While 14 of the 16 unimmunized control animals became infected, only 6 of 16 ALVAC-immunized and 11 of 17 MVA-immunized animals became infected (Marthas et al., unpublished data). However, the immunologic correlates of protection are unclear, as neither titers of neutralizing antibodies, total SIV-specific antibodies (by enzyme-linked immunosorbent assay), nor SIV-specific interferon-γ-producing cells (by enzyme-linked immunospot assay) correlated with protection. Thus, further research is warranted to define the immune responses that are induced by these poxvirus-based vectors, including the potential role of innate immune responses.

In additional neonatal vaccine experiments, the safety and efficacy of DNA prime/protein boost vaccination were tested in neonatal macaques against SHIV-vpu+; priming was with 5 DNA expression vectors encoding multiple virus genes and boosting with multimeric HIV-1 gp160. 41 The study was performed in parallel with one in adult macaques. 42 Following SHIV-vpu+ challenge, complete or partial containment of infection was seen in 27% of animals given DNA priming/protein boosts and in 75% of those given boosts only. Rechallenge of animals that had contained the first challenge virus with homologous virus 4 months later resulted in rapid viral clearance or low viral loads, and upon subsequent rechallenge with heterologous, pathogenic SHIV89.6P, no or limited infection with this virus and normal CD4 counts were seen in two thirds of the animals. While these experiments are complicated by the sequential rechallenge procedures, humoral as well as cellular immune mechanisms apparently contributed to viral containment. These data indicate that immunogenicity and efficacy of this first-generation candidate AIDS vaccine was not affected when vaccination was started in the neonatal period as compared with later in life. 41

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Human Trials: The Future

Of the numerous previous clinical trials of HIV vaccine products in humans, very few have been tested in children (for a review, see Safrit 43). These include early studies with HIV envelope protein products and more recently poxvirus priming (ALVAC) with protein boosting. 43 The products used in these studies proved safe but only weakly immunogenic. It is important to note that the limited immunogenicity of the products in children was similar to that observed in adults and this immunogenicity was induced in a rapid course of injections within the first months of vaccination. Currently, there are several products either in or beginning phase 1 trials in adults, with many more on the horizon. At a minimum, these include DNA-, viral vector-, and protein-based products.

The candidate HIV vaccines most likely to move from the animal models into clinical trials in human adults and then into infants in a reasonable time frame are multigene recombinant viral vector products based on MVA. MVA was developed as an alternative smallpox vaccine after attenuation by >500 passages in chick embryo fibroblasts and has been given safely to >160,000 humans in Germany. 44 As a result of the multiple passages, this vector has a substantially improved safety profile because the virus deleted large portions of its genome, including genes responsible for immune evasion, and was rendered unable to replicate in mammalian cells. 45 This replicative defect was subsequently determined to be a late-stage event, thereby allowing viral gene expression, but not virion assembly. 46 Thus, not only is the MVA vector safe, it can also efficiently express the genes that would be required of a vector to stimulate an immune response. The fowlpox vectors also do not appear to have replicative potential in human cells. A study in the planning stages could be the first to make use of MVA and fowlpox HIV vaccines in infants.

The trial, known as PACTG 1033, is a planned phase 1 study of the safety and immunogenicity of multivalent MVA and fowlpox vaccines in HIV-1-infected infants who have achieved control of HIV replication following early intensive antiretroviral therapy. The trial is a collaboration between Therion Biologics and the University of Massachusetts. As an element of unique design, the MVA and fowlpox vectors have been engineered to express env, gag, tat, rev, and nef-RT genes of an HIV-1 strain isolated from an infected infant. The trial design is to give the MVAs at time zero and 1 month, followed by fowlpox boosts at 2 and 6 months after the first MVA. The use of different vectors to deliver the HIV antigens should increase the chances of successful boosting of antiviral immunity by lessening the antivector immune response. Parallel trials in HIV-infected adults (in the ACTG) and uninfected adults (in the HVTN) will provide supporting safety and immunogenicity data. Once they are deemed safe and immunogenic, future plans would be to move into a phaseI/II trial of the products in neonates born to HIV-infected women, much the way the original PACTG trials progressed (Luzuriaga, personal communication, 2003).

Another trial that is likely to start within a relatively short timeframe is HPTN 027, which would be conducted in the HIV Prevention Trials Network. The design of this trial is still under discussion, but the candidate ALVAC-vectored vaccines, very similar in design to those tested in infant macaques by Marthas et al., would be tested in a breast-feeding population of infants. The candidate vaccine, which has been extensively tested in adults in Thailand (vCP1521), would be studied in infants born to HIV-infected mothers in Uganda. A key issue that will be addressed in this trial will be a safety issue related to maintenance of good immune responses to the vaccines in the standard childhood program for immunizations.

Also in the preplanning stages with the PACTG is a novel immunotherapeutic agent, known as DermaVir, that is designed to deliver a replication- and integration-defective HIV DNA to dendritic cells after topical skin application. This multigenic DNA vaccine candidate is formulated with polyethylenimine-mannose in a glucose solution, specifically designed to transduce Langerhans cells on the surface of the skin. These cells should then migrate to the lymph node and mature to antigen-expressing dendritic cells, ultimately eliciting HIV-specific T-cell immunity. An SIV version of the product has been in preclinical testing in chronically SIV-infected rhesus macaques with some success. In an antiviral treatment interruption model, DermaVir induced suppression of viral replication during treatment interruptions even in some macaques that had already progressed to AIDS. The control of viral load in the absence of therapy was associated with augmented SIV-specific CD8 and CD4 T cells as measured by interferon-γ intracellular cytokine assay (Lisziewicz, personal communication).

Additional products in the HIV Vaccine Trials Network pipeline include multiple DNAs, viral vectors, and recombinant proteins, some of which are currently in phase 1 trials in adults. Most of the current strategies rely on the idea that priming the immune system with 1 candidate HIV vaccine product and a boosting with a different candidate vaccine will be more effective than multiple shots of a single type of vaccine. Thus, it is proposed that specific combinations of these products will be the most effective and it will be necessary to test various products in different sequential patterns to optimize an HIV vaccine approach. It will be important to rapidly identify the safe, well-tolerated, and immunogenic products and strategies among these while thinking concurrently about pediatric trials. In support of this timing, many pediatricians think that adult phase 1 safety data are sufficient preliminary data to initiate HIV vaccine trials in children (Luzuriaga, personal communication).

In summary, there is an urgent need to develop improved strategies to prevent HIV-1 transmission during breast-feeding. Over the course of the workshops, several products imminently available for clinical testing with promising preclinical data were identified that could enter clinical pediatric trials over the next year or two (including monoclonal antibody combinations and vaccines). Timely conduct of clinical trials to test the safety and efficacy of these products in infants coupled with continued research to understand the pathogenesis of MTCT and to identify potential correlates of protection will be important. While no one is advocating putting all of the potentially available HIV-1-specific antibodies or candidate HIV-1 vaccines into children, we should err on the side of studying more rather than fewer immunoprophylaxis products or vaccines and we must be careful not to discard products altogether without consideration of how they might work either as individual products or as combination modalities in the prevention of MTCT. We should keep in mind that the complex regimen of zidovudine in the PACTG 076 trial, which has so profoundly decreased the number of perinatal HIV infections in developed countries, lowered viral load in the mothers only by about a half a log. This may also be true for MTCT during the breast-feeding period.

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Keywords:

immunoprophylaxis; prevention mother-to-child transmission; neonates; vaccines

© 2004 Lippincott Williams & Wilkins, Inc.

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