AIDSWEEKLY Plus, 29 July 1996
Daniel J. DeNoon, Senior Editor

Findings from smaller trials only recently completed provide tantalizing hints that what has come to be called the "prime/boost" approach may yield an effective vaccine.

"To see whether these findings are relevant, we need to conduct large-scale clinical trials," said Mary Lou Clements of the Center for Immunization Research, Baltimore, Maryland.

Clements was one of two scientists to present the results of Phase I/II clinical trials of the strategy at the XI International Conference on AIDS, held July 7-12, 1996 in Vancouver, British Columbia, Canada.

The strategy employs two candidate HIV vaccines: priming with recombinant canarypox expressing HIV antigens (ALVAC, Virogenetics/Pasteur-Merieux) followed by boosting with a recombinant HIV gp120 subunit vaccine (rgp120[MN] in MF59 adjuvant, Chiron/Biocine).

Earlier this year, NIAID Director Anthony Fauci predicted that if Phase II trials are successful - defined as confirmation of cytotoxic lymphocyte (CTL) and antibody induction, safety, and either protection of primates in concurrent challenge studies or evidence of clinical efficacy - Phase III trials could begin as early as the third quarter of 1998.

So far, early studies have been highly successful. Human trials have proven that the approach is safe and can induce both CTL and neutralizing antibodies. Moreover, some monkeys that received analogous canarypox vaccines remained uninfected after infectious-virus challenge.

The most recent of the rapid advances were announced in separate presentations by Clements and Lawrence Corey of the University of Washington, Seattle, at the XI International Conference on AIDS, held July 7-12, 1996 in Vancouver, British Columbia, Canada.

Clements reported results from an immunogenicity study of an early version of ALVAC that expressed only the HIV-1[MN] gp160 envelope precursor protein (ALVAC-HIVgp160).

Study participants were healthy, HIV seronegative volunteers.

The study compared different intramuscular doses and schedules of ALVAC-HIVgp160 alone (four doses), ALVAC-HIVgp160 followed by rgp120 (two doses of each), or rgp120 alone (four doses). Control subjects received an ALVAC canarypox vaccine carrying a rabies glycoprotein either alone (four doses) or boosted with rgp120 (two doses of each).

Vaccinations were performed at study months 0, 1 or 2, 6 or 9, and 12. At each vaccination participants received either 10(6) 50% tissue-culture infectious doses (TCID[50]) of ALVAC-HIVgp160 alone (10 subjects), 10(6) TCID[50] ALVAC- HIVgp160 + 50 (micro)g rgp120 (nine subjects), 10(7) TCID[50] ALVAC-HIVgp160 alone (18 subjects), 10(7) TCID[50] ALVAC- HIVgp160 + 50 (micro)g rgp120 (29 subjects), or 50 (micro)g rgp120 alone (nine subjects).

Except for pain at the site of inoculation, the vaccines were "very well tolerated," Clements said.

Boosting with rgp120 was essential for consistent elicitation of high anti-HIV antibody titers as well as for elicitation of HIV-neutralizing antibodies.

Antibodies capable of neutralizing not only the MN strain of HIV-1 but also the heterologous SF2 strain of HIV-1 appeared in all subjects who received ALVAC-HIVgp160 plus rgp120.

"The combination of ALVAC and rgp120 produced broader and higher levels of antibody-dependent cellular cytotoxicity, V3 antibodies, and neutralizing antibodies versus primary and laboratory isolates of HIV," Clements reported.

The trial conducted by Corey and colleagues evaluated a more sophisticated ALVAC vaccine in 76 seronegative volunteers at low risk of HIV infection.

Also based on the Virogenetics canarypox virus vector, this vaccine (vCP205) expresses the p55 Gag protein, the p15 protease protein, and the transmembrane region of the gp41 glycoprotein from the LAI strain of HIV-1 as well as the gp120 envelope glycoprotein from the MN strain of HIV-1.

Only part of the gp41 antigen is used in the vaccine so that investigators can easily determine whether an individual has become infected with wild-type virus.

Participants received 10(5.8) TCID[50] vCP205 at study months 0,1, 3, and 6 or at months 0, 1, and 6 followed by 50 (micro)g rgp120 in MF59 (Chiron/Biocine) at months 9 and 12. Control subjects received the ALVAC rabies vaccine.

After three doses of vCP205, 70 percent of subjects had CD8 cytotoxic lymphocyte (CTL) responses to HIV Gag protein. After completion of vaccinations, Corey said, 45 to 50 percent of subjects developed a CTL response.

Again, boosting of the ALVAC vaccine with rgp120 elicited neutralizing antibodies. Other results:

• The vCP205 vaccine is safe and immunogenic.
• CTL responses occur prior to the appearance of antibody responses.
• The 0, 1, 3, and 6 month vaccination schedule tended to be more immunogenic than the 0, 1, and 6 month schedule, but the difference was not statistically significant.

"These results suggest that a vaccine regimen consisting of a canarypox vector followed by a recombinant subunit protein will elicit HIV-specific CTL and neutralizing antibodies in seronegative subjects," Corey said.

He noted that his group is currently conducting a study using a 1-log[10] higher dose of vCP205.

"This study is intended to answer two questions," Corey said. "Will it [the higher dose] increase the frequency and durability of the CTL response? And will boosting it enhance the humoral effects of the subunit vaccine more?"

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