BACKGROUND
A safe, effective vaccine is essential to end HIV. A canarypox/protein HIV
vaccine regimen showed modest efficacy at reducing infection in Thailand. An
analogous regimen using HIV-1 subtype C virus demonstrated potent humoral
and cellular responses in a Phase 1/2a trial and triggered a Phase 2b/3
double-blinded trial to assess the safety and efficacy of this regimen in
South Africa.
METHODS
We enrolled and randomized 5,404 healthy, HIV-uninfected 18-35-year olds at
14 sites to vaccine (2,704 participants) or placebo (2,700 participants)
between 26 October 2016 and 21 June 2019. The vaccine regimen consisted of
two ALVAC-HIV (vCP2438) (expressing HIV-1 subtype C
env,
clade B
gp41
,
gag
and
pro)
immunizations at months 0 and 1, with booster
immunizations of ALVAC-HIV plus bivalent subtype C gp120 protein/MF59
adjuvant at months 3, 6, 12 and 18. Efficacy was evaluated by HIV testing
every 3 months.
RESULTS
In January 2020, pre-specified non-efficacy criteria were met at an interim
analysis; further vaccinations were subsequently halted. The vaccines were
safe and well-tolerated in the study population (median age 24, 70%
female-sex-at-birth). Over the primary 24-month follow-up, there were 133
infections among placebo recipients and 138 among vaccinees (hazard ratio =
1.02; 95%CI, 0.81-1.30; P=0.84). Pre-specified subgroup analyses
demonstrated no difference in efficacy by sex or when restricting to
follow-up post-4
th
vaccination, and no difference amongst
female-sex-at-birth by age, BMI, prevalent STIs, behavioral risk score or
region.
CONCLUSIONS
The ALVAC/gp120 regimen did not prevent HIV infection in South Africans
despite prior evidence of immunogenicity.
ClinicalTrials.gov (NCT02968849)
A randomized double-blind Phase I Trial was conducted to evaluate safety, tolerability, and immunogenicity of a yellow fever (YF)-dengue 2 (DEN2) chimera (ChimeriVax™-DEN2) in comparison to that of YF vaccine (YF-VAX ® ). Forty-two healthy YF naïve adults randomly received a single dose of either ChimeriVax™-DEN2 (high dose, 5 log plaque forming units [PFU] or low dose, 3 log PFU) or YF-VAX ® by the subcutaneous route (SC). To determine the effect of YF preimmunity on the ChimeriVax TM -DEN2 vaccine, 14 subjects previously vaccinated against YF received a high dose of ChimeriVax™-DEN2 as an open-label vaccine. Most adverse events were similar to YF-VAX ® and of mild to moderate intensity, with no serious side-effects. One hundred percent and 92.3% of YF naïve subjects inoculated with 5.0 and 3.0 log 10 PFU of ChimeriVax TM -DEN2, respectively, seroconverted to wt DEN2 (strain 16681); 92% of subjects inoculated with YF-VAX ® seroconverted to YF 17D virus but none of YF naïve subjects inoculated with ChimeriVax-DEN2 seroconverted to YF 17D virus. Low seroconversion rates to heterologous DEN serotypes 1, 3 and 4 were observed in YF naïve subjects inoculated with either ChimeriVax™-DEN2 or YF-VAX ® . In contrast, 100% of YF immune subjects inoculated with ChimeriVax™-DEN2 seroconverted to all 4 DEN serotypes. Surprisingly, levels of neutralizing antibodies to DEN 1, 2 and 3 viruses in YF immune subjects persisted after 1 year. These data demonstrated that (1) the safety and immunogenicity profile of the ChimeriVax™-DEN2 vaccine is consistent with that of YF-VAX ® , and (2) preimmunity to YF virus does not interfere with ChimeriVax TM -DEN2 immunization, but induces a long lasting and cross neutralizing antibody response to all 4 DEN serotypes. The latter observation can have practical implications toward development of a dengue vaccine.
Abstract. Four serotypes of monovalent live attenuated dengue virus vaccine candidates were tested for reactogenicity and immunogenicity in 49 flavivirus non-immune adult human volunteers. The four monovalent candidates were then combined into a tetravalent formulation and given to another 10 volunteers. Neutralizing antibody seroconversion rates after a single-dose monovalent vaccination ranged from 53% to 100%. Solicited reactogenicity was scored by each volunteer. A composite index, the Reactogenicity Index, was derived by these self-reported scores. Reactogenicity differed among the four serotype candidates with serotype-1 associated with the most vaccine related side effects. A second dose of monovalent vaccines at either 30 days or 90 days was much less reactogenic but did not significantly increase seroconversion rates. Seroconversion rates in the 10 volunteers who received a single dose of tetravalent vaccine ranged from 30% to 70% among the four serotypes. Similar to the monovalent vaccines, a second dose of the tetravalent vaccine at one month was less reactogenic and did not increase seroconversion. A third dose of the tetravalent vaccine at four months resulted in three of four volunteers with trivalent or tetravalent high-titer neutralizing antibody responses.
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