AIDSWEEKLY Plus, Monday, 30 June 1997
Daniel J. DeNoon, Senior Editor

Only three immunizations raised long-lasting neutralizing antibodies capable of protecting chimpanzees against challenge with infectious virus of the same type as that used for booster immunization.

The animals were vaccinated using the prime/boost approach: they received intranasal priming immunization(s) with Wyeth-Ayerst's adenovirus-HIV-1[MN]gp160 followed by intravenous boosting with Chiron's HIV-1[SF2]gp120 in MF59 adjuvant.

Four of five immunized chimpanzees developed either neutralizing antibody or lymph-node cytotoxic lymphocyte (CTL) against HIV. A year after inoculation, these four animals resisted low-dose HIV-1[SF2] challenge (all control animals were infected). A year after low-dose challenge - with no intervening immunizations - three of the five immunized chimps resisted high-dose challenge with HIV-1[SF2].

"Our results further validate the live vector priming/subunit booster approach and should stimulate interest in assessing this combination vaccine in humans, the natural host of adenovirus," wrote Wyeth-Ayerst researcher Michael D. Lubeck and colleagues in the journal Nature Medicine ("Long- Term Protection of Chimpanzees against High-Dose HIV-1 Challenge Induced by Immunization," Nature Med, 1997;3(6):651- 8).

Previous studies have demonstrated vaccine protection of chimpanzees against HIV infection, but all have required multiple immunizations and challenge soon after vaccination.

Lubeck et al. noted that adenoviruses are a particularly attractive candidate as vaccine vectors for HIV not only because they can induce both humoral and cellular immunity, but also because they replicate at mucosal sites in the gut and respiratory tract. Moreover, the fact that there are 45 antigenically distinct viral serotypes assures that multiple types could be used as vectors if sequential vaccinations are required.

An earlier Wyeth-Ayerst adenovirus/HIV recombinant encoded gp160 from the LAI strain of HIV. This vaccine, administered to chimpanzees in prime/boost experiments with a baculovirus- produced HIV-1[LAI] gp160 subunit, induced only transient neutralizing antibodies.

Far better results were seen in prime/boost studies with the adenovirus-HIV-1[MN]/HIV-1[SF2]gp120 combination. To determine the optimal number of immunizations and to assess protective efficacy, Lubeck et al. immunized six female chimpanzees.

* Animal 1P received one priming vaccination with Ad5-gp160 at week 12 and gp120 boosts at weeks 38 and 48.

* Animals 2P[A] and 2P[B] received two priming vaccinations (Ad5-gp160 at week 12 and Ad7-gp160 at week 24) with one gp120 boost at week 48.

* Animal 3P received three priming vaccinations (Ad5-gp160 at week 0, Ad7-gp160 at week 12, and Ad4-gp160 at week 24) with one gp120 boost at week 48.

* Animal 2P[POS] was the only animal in the study with significant pre-existing antibody to adenovirus. This chimpanzee received two priming vaccinations (the three adenovirus/HIV recombinants Ad5,7,4-gp160 at weeks 12 and 24) with one gp120 boost at week 48.

* Control animal 3C was primed with adenovirus vector only (Ad5 at week 0, Ad7 at week 12, and Ad4 at week 24) followed by mock boosting with MF59 adjuvant only at week 48.

* Naive control animal C received no immunizations. "High-titered neutralizing antibodies to MN and SF2 laboratory isolates, associated with good replication of adenovirus recombinants, developed in chimpanzees 2P[A] and 3P and in chimpanzee 1P after booster immunizations, but not in chimpanzees 2P[B] and 2P[POS]," Lubeck et al. reported. "Sporadic HIV-1 specific CTL activity was detected in peripheral blood lymphocytes (PBLs) of all immunized chimpanzees over the course of immunization. The highest levels were seen in chimpanzees 2P[B] and 2P[POS], which lacked neutralizing antibodies, and the lowest were in chimpanzee 3P, which had the highest neutralizing-antibody titers."

Only one animal (2P[B]) had lymph-node cells capable of >10 percent specific lysis of autologous cells expressing HIV envelope.

Because it failed to develop neutralizing antibodies or CTL, animal 2P[POS] did not receive low-dose challenge. All other vaccinated animals were injected with 1 ml of 1:40 dilution of HIV-1[SF2] 52 weeks after immunization. Control immunized animal 3C became infected (as did four other controls in other experiments); animals 1P, 2P[A], 2P[B], and 3P did not become infected.

Forty-six weeks after the low-dose challenge, all animals were injected with 1 ml of a 1:5 dilution of the HIV-1[SF2] challenge stock. Animal 2P[POS] received a third Ad-gp160 vaccination two weeks before challenge; none of the other animals received any new vaccinations.

Naive control animal C and 2P[POS] became infected at similar rates. Animal 2P[B] became infected, but infection proceeded more slowly than in animal C. Animals 1P, 2P[A], and 3P remained uninfected.

Interestingly, animal 3C - which became infected after low-dose challenge - apparently resisted high-dose challenge.

"Thus, a low-dose infection seemed to protect against subsequent homologous high-dose challenge," Lubeck et al. concluded.

Because the challenge stock of virus was propagated in human cells, the researchers checked to see whether immunity was mediated by chimpanzee immune responses to human cellular antigens. This phenomenon has compromised a number of earlier studies. But sera obtained from the animals at the time of challenge and two and four weeks after both the low- and high- dose challenges contained no antibodies to human HLA-RR1, HLA- DR4, or (beta)[2]-microglobulin.

Lubeck et al. concluded that their study provided four important advances in the quest for an AIDS vaccine:

* Persistent neutralizing antibodies can be induced in as few as three immunizations.

* Immunization induced high-titer neutralizing antibodies that recognized clinical isolates. In vitro studies showed that the primary isolate BZ167 could be neutralized in vitro by antibodies from the immunized animals. "Such antibody activities have not previously been demonstrated in other approaches, but likely are crucial for further vaccine development," Lubeck et al. wrote.

* Animal 2P[B] resisted low-dose challenge despite the lack of neutralizing antibodies. This chimpanzee's CTL responses apparently were sufficient for protection.

* The most important finding, Lubeck et al. suggested, was that long-lasting protection extended for a year after the last immunization.

The authors suggested that the adenovirus vaccine could be improved by the addition of other HIV-1 antigens such as Gag and Nef.

This work was supported by National Institutes of Health grants AI 32424 and AI 36085 and by funds from the Research Center for AIDS and HIV Infection from the Department of Veterans Affairs.

The corresponding author for this study is Michael D. Lubeck; his present address is Wyeth-Lederle Vaccines & Pediatrics, P.O. Box 304, Marietta, Pennsylvania 17547.

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