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Analysis of the Safety and the Immunogenicity of a Pox Vector-based Vaccine Expressing Env, Gag, Pol, and Nef Proteins of HIV-1 Subtype C
P -A Bart*1, A Harari1, M Khonkarly1, G Tapia1, E Medjitna-Rais1, L Poupon1, M J Frachette2, S McCormack3, P Liljeström4, H Wolf5, G Pantaleo1, and EUROVACC
1Univ Hosp, Lausanne, Switzerland; 2Aventis Pasteur, Lyon, France; 3Med Res Council Clin Trials Unit, London, UK; 4Karolinska Inst, Stockholm, Sweden; and 5Univ of Regensburg, Germany
Background: EV01 is a randomized placebo-controlled phase
I trial to assess NYVAC-HIV C, a recombinant NYVAC (vP866) strain with an
insert containing gag-pol-nef polyprotein and env, both derived from the
Chinese R5 HIV clade-C virus (97CN54). The safety and immunogenicity of the
candidate vaccine are described.
Methods: We immunized 24 healthy low-risk HIV-negative
volunteers (12 in China; 12
in the United Kingdom)
with NYVAC-HIV C (n = 20) or placebo (n = 4) at weeks 0 and 4. Local and
systemic adverse events were assessed at 10 minutes, 1 hour, and 1 to 7 days
after vaccination. The immunogenicity was evaluated by interferon-γ
ELISpot assays on cryo-preserved blood mononuclear cells at weeks 0, 4, 6, 8,
24, and 48 with 8 pools of 49 to 61 peptides (15 mers overlapping by 11)
encompassing the gag-pol-nef, and env regions. All ELISpot assays had a
background below 50 spots/106 cells and a positive control above 500
spots/106 cells but responses were regarded as positive only if they
were at least 4-fold the background and higher than 55 spots/106
cells.
Results: Solicited adverse effects were observed in
92% of the 24 participants after both vaccinations–71% grade I and 21% grade II–and
more frequently after the second vaccination. No grade III
or IV adverse effect was reported. Vaccine-specific responses were generated in
5 of the 10 vaccinees from China
(for technical reasons, results are not available for the 10 vaccinees from the
United Kingdom
until week 24). All 5 volunteers (50%) gave vaccine-specific positive responses
at week 6, while only 1 was positive at week 4, 3 at week 8, and 1 at week 24.
In addition, positive ELISpot responses were observed at week 24 in 2 of 10
vaccinees from the United
Kingdom. No response was detected at week 48.
Of interest, 4 volunteers showed consistent positive responses to 1 (ENV1) of the 2 peptide pools covering env, while
responses to the other env pool (ENV2)
were also found in 2 volunteers. Furthermore, responses to both gag pools were
also observed in 2 subjects, and responses to the nef pool in 2 volunteers. Of
note, the fine mapping of the epitopes showed that both CD4 and CD8 T-cell
responses were generated and some of these epitopes had already been described
in HIV-infected patients. Of interest, vaccine-specific proliferating cells
were also observed.
Conclusion: NYVAC-HIV C was well
tolerated and specific responses were observed in 50% of the subjects from
China
with a peak at week 6. Env-specific responses were found in all responders and
additional responses against peptides of other proteins were detected in 60% of
responders.
Keywords: HIV vaccine; Pox-virus vector; Immunogenicity
