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Data derived from the Science Watch/Hot Papers database and the Web of Science (ISI, Philadelphia) show that Hot Papers are cited 50 to 100 times more often than the average paper of the same type and age. D.H. Barouch et al., "Control of viremia and prevention of clinical AIDS in rhesus monkeys by cytokine-augmented DNA vaccination," Science, 290:486-92, Oct. 20, 2000. (Cited in 130 papers) J.R. Mascola et al., "Protection of macaques against vaginal transmission of a pathogenic HIV-1/SIV chimeric virus by passive infusion of neutralizing antibodies," Nature Medicine, 6:207-10, Feb. 1, 2000. (Cited in 132 papers) T.W. Baba et al., "Human neutralizing monoclonal antibodies of the IgG1 subtype protect against mucosal simian-human immunodeficiency virus infection," Nature Medicine, 6:200-6, Feb. 1, 2000. (Cited in 115 papers) HIV vaccine strategies generally fall into two categories: those aimed at raising antibody responses, and those aimed at inducing high numbers of cytotoxic T lymphocytes (CTLs), or killer T cells. In the early years of HIV vaccine development most approaches focused on antibodies. But researchers had difficulty developing vaccine immunogens that elicit an effective antibody response. The Hot Paper by Dan Barouch and colleagues, Massachusetts General Hospital (MGH), used rhesus monkeys and has helped the CTL strategy gain prominence.1 In that same year, two groups published proof-of-principle companion papers, which also became Hot Papers; their results implied that an antibody-boosting vaccine strategy also could be successful.2,3 Subsequent work has shown that both approaches have advantages and drawbacks, and that a combined strategy may provide the best level of protection against HIV. The immune system's CTL response arm had been shown to be particularly important for controlling HIV replication. Researchers at MGH began investigating whether vaccines specifically designed to augment this type of response would be effective at stymieing simian-human immunodeficiency virus (SHIV) infection in monkeys. T-CELL SUCCESS The group used a plasmid DNA vaccine that has the potential to raise T-cell responses. When injected into muscle cells, the plasmids express an encoded antigen. If all goes as intended, the immune system generates an immune response tailored to fight off SHIV. But the DNA vaccine alone triggers only a modest T-cell response. According to Barouch, MGH research fellow in medicine, his lab was the first to significantly augment the DNA vaccine-elicited immune response with cytokines, namely IL-2 fused to the Fc portion of an immunoglobulin molecule. The IL-2/Ig fusion has better avidity and staying power than the IL-2 alone. Adding the cytokines significantly enhanced the potency of the DNA vaccine. The eight infected monkeys that received both DNA and IL-2 had rapidly controlled viral replication below detectable levels. "They were not protected against infection, but ... [they were protected] against high levels of viral replication, CD4 T-cell loss, clinical disease progression, and death," explains Barouch. Barouch cites two major developments in the CTL HIV vaccine field in the past two years--one from Emory University4 and another from Merck & Co.5 Like Barouch's, these teams focused on optimizing T-cell responses in monkeys. But they used recombinant MVA (modified vaccinia virus Ankara) or recombinant adenovirus vectors to boost immune responses rather than the cytokines used in Barouch's study. Thus far, the vaccines have developed a similar protection level as Barouch's. "Essentially our results have been replicated by other groups using other vaccines that are specifically designed to elicit potent CTL responses," he says. Not all recently reported developments have been encouraging. The same January issue of Nature that included the Merck results also contained a follow-up paper from Barouch's group reporting that one of the eight infected monkeys, whose DNA-IL-2 vaccine had been keeping the virus in check, had a breakthrough of viral replication, got sick, and died.6 Viral sequencing revealed that a mutation had developed in the virus, allowing for viral escape from CTL recognition, which led to unchecked viral replication and disease progression. "Even though restricted to one animal, the implications to the field were quite profound," explains Barouch. "Viral escape from CTL may be a significant practical limitation of these CTL-based AIDS vaccines." Photo: Courtesy of Ruth Ruprecht Ruth Ruprecht THE RETURN OF ANTIBODIES Prior to the publication of the macaque companion papers from groups led by John Mascola2 and Harvard Medical School professor of medicine Ruth Ruprecht,3 murine models had shown that passive transfer of monoclonal antibodies (mAbs) could protect against an HIV challenge. "But there really had not been that type of confirmation in a primate model," says Mascola, now a deputy director of the National Institutes of Health's Vaccine Research Center. "So a number of groups started to pursue that question, whether antibody, and what kind of antibody, would protect against HIV." Prior to these papers, antibodies also had been shown to confer protection in a primate model after intravenous virus challenge7. But responses to mucosal challenge remained unexplored. According to Mascola, his and Ruprecht's studies were proof of concept that potent neutralizing antibodies could protect against mucosal infection, the most prevalent mode of HIV transmission. "What that tells the vaccine field is [that] in addition to the DNA vaccine strategies that Barouch et al. used, we'd also like our vaccine to produce high antibody levels," says Mascola. Using the SHIV model system, Mascola showed that HIV-specific antibody could protect against vaginal mucosal challenge; Ruprecht's group studied an oral mucosal system. Unlike the CTL DNA vaccine approach, the immunity conferred here was passive, meaning that within months, the antibodies administered are metabolized and eliminated from the monkey's system, leaving the newly primed immune system to fend for itself. The results of Mascola's work were twofold. His group showed that infusing a combination of potent neutralizing antibodies would afford complete protection against viral challenge, a level of defense often referred to as sterilizing immunity. Large amounts of antibody produced sterilizing immunity; lower amounts or less potent antibodies afforded partial protection. In other words, although the monkey became infected, the peak viral load and the viral load set point were both lower. Mascola's group used a combination of antibodies--two human mAbs and an HIV immunoglobulin, which is a polyclonal antibody derived from the plasma of HIV-infected patients. As predicted by in vitro studies, the more antibodies administered, the more effective the treatment. All three together conferred the highest level of sterile protection; a single antibody conferred partial protection by lowering viral load. All antibody-treated macaques were either completely or partially protected. Mascola's group verified complete protection at post mortem examinations after six months of infection. Graphic: Courtesy of John Mascola MONKEY BUSINESS: Plasma SHIV RNA (a) and peripheral CD4% (b) for four groups of monkeys after antibody infusion and vaginal SHIV89.6PD challenge. Percent CD4 indicates percent of peripheral blood lymphocytes with CD4+ phenotype by flow cytometry. Open symbols signify monkeys that are completely protected against infection. The passively infused antibody is noted at the top of each graphic. (Reprinted with permission, Nature Medicine, 6:207-10, 2000). Unlike the Mascola study, the Ruprecht work employed only mAbs. Ruprecht explains that her group chose this route to find a sound basis for vaccine development. If successful, they could identify the epitopes that an antibody-based vaccine could be designed to mimic. "With polyclonal antibodies, you don't know which antibody in the mixture is doing the job," says Ruprecht. Ruprecht's group treated four pregnant macaques with IgG1 mAbs; all four macaques, including the offspring, were protected against intravenous SHIV challenge after delivery. The infants received mAbs, and then were challenged orally with SHIV. In the six months that followed, researchers found no evidence of virus infection. To ensure that different HIV strains cannot circumvent antibody recognition, Ruprecht selected human mAbs that identify areas on the viral envelope glycoprotein that do not tend to change. Follow up research from Ruprecht's group suggests that a combined vaccine approach, incorporating both antibodies and CTLs, has the best chance of success. Experimental data suggest that when one defense mechanism fails, another one can take over and stop viral spread.8 In hopes of achieving a higher level of protection, Mascola's and Barouch's groups are collaborating on a study that combines the cytokine- augmented DNA vaccine with the passive infusion of antibody. "Nature has devised humoral immunity, and nature has devised cellular immunity," says Ruprecht. "And I really think we should enlist as many defense mechanisms as we possibly can." Eugene Russo (erusso@the-scientist.com) is a contributing editor. References 1. D.H. Barouch et al., "Control of viremia and prevention of clinical AIDS in rhesus monkeys by cytokine-augmented DNA vaccination," Science, 290:486-92, Oct. 20, 2000. (Cited in 130 papers) 2. J.R. Mascola et al., "Protection of macaques against vaginal transmission of a pathogenic HIV-1/SIV chimeric virus by passive infusion of neutralizing antibodies," Nature Medicine, 6:207-10, Feb. 1, 2000. (Cited in 132 papers) 3. T.W. Baba et al., "Human neutralizing monoclonal antibodies of the IgG1 subtype protect against mucosal simian-human immunodeficiency virus infection," Nature Medicine, 6:200-6, Feb. 1, 2000. (Cited in 115 papers) 4. R.R. Amara et al., "Control of a mucosal challenge and prevention of clinical AIDS in rhesus monkeys by a multiprotein DNA/MVA vaccine," Science, 292:69-74, 2001. 5. J.W. Shiver et al., "Replication-incompetent adenoviral vaccine vector elicits effective anti-immunodeficiency-virus immunity," Nature, 415:331-5, 2002. 6. D.H. Barouch et al., "Eventual AIDS vaccine failure in a rhesus monkey by viral escape from cytotoxic T lymphocytes," Nature, 415:335-9, 2002. 7. J.R. Mascola et al., "Protection of macaques against pathogenic simian/human immunodeficiency virus 89.6PD by passive transfer of neutralizing antibodies," Journal of Virology, 73:4009-18, 1999. 8. R.A. Rasmussen et al., "Neutralizing antibodies as a potential secondary protective mechanism during chronic SHIV infection in CD8+T-cell-depleted macaques," AIDS, 16:829-38, April 12, 2002.

Scientists Combine Two Approaches to Thwart the Spread of HIV

Sep 15, 2002

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