Safety and immunogenicity of yellow fever vaccine in HIV+ patients: ANRS EP46 NOVAA

Background: Yellow fever vaccine (YFV) uses a live attenuated viral strain and is contra-indicated in HIV-infected patients with < 200 CD4 cells/mm3. Whether YFV is safe and efficacious in patients with higher CD4 count remains to be clarified. We performed a prospective, comparative, non randomized study to assess safety and immunogenicity of YFV in uninfected (HIV−) and HIV-infected (HIV+) adults with CD4 count >350/mm3.
Methods: 40 YFV-naïve HIV+ adults under antiretroviral therapy (ART) with CD4 >350/mm3 and plasma HIV RNA < 50 cp/ml for at least 6 months, and 31 HIV− healthy adults received primary vaccination with YFV 17D strain. Follow-up was performed at day 7, 14, 28, 91, 365. Safety was assessed by grading clinical and biological adverse events (AEs), detection of YFV viremia using RT‑PCR, CD4 count and plasma HIV RNA levels. Serologic response was assessed by neutralizing antibody titers using a reference plaque reduction neutralizing test (PRNT) and a new pseudotype based neutralization assay, with protection associated titers >10 and >95% neutralizing activity, respectively.
Results: At baseline, HIV+ subjects were mostly male (95%), median age: 44 years, median CD4: 702/mm3 (IQR 553, 840), 23% were CDC stage C. HIV− patients were mostly female (88%), median age: 35 years, median CD4: 902/mm3 (IQR 635, 1247). Adverse events were reported by 42% of HIV− and 30% of HIV+, mostly headaches, asthenia, myalgia and local reactions of grades 1 or 2. None of the 3 SAE reported, with 1 death, was related to vaccination.76% of HIV− and 82% of HIV+ subjects had positive YFV viremia at D7 only. There was a significant decrease in CD4 count in both groups at D7 which was more pronounced in HIV− than in HIV+ patients (261.5 vs 111.5 cells decrease from baseline, respectively, p=0.0003). There was no HIV breakthrough during follow-up. All patients (100%) in both arms developed protective neutralizing antibody levels with both assays since day 28 and for a year after injection.
Conclusions: In HIV+ patients with CD4 >350/mm3 and suppressed viral replication on ART, YFV was as safe and immunogenic as in HIV− subjects. Long-term follow-up will tell whether protection is maintained over time.

N. Colin de Verdière1, V. Meiffrédy2, C. Durier2, O. Launay3, S. Matheron4, S. Mercier-Delarue5, A. Boulay5, J.-M. Molina1, F. Simon5, ANRS EP46 NOVAA Group
1Saint-Louis Hospital , APHP, Infectious Diseases, Paris, France, 2SC10-US019, INSERM, Villejuif, France, 3Cochin Hospital, APHP, CIC de Vaccinologie Cochin Pasteur, Paris, France, 4Bicêtre Hospital, AP-HP, Infectious Diseases, Paris, France, 5Saint-Louis Hospital, APHP, Microbiology, Paris, France