Zika: another virus, another vaccine...

 In the midst our current Covid scourge, many of us may have lost sight of another recent viral attack (of considerably less magnitude), that of Zika virus. A new adenovirus-based vaccine by Janssen/J&J seems likely to be beneficial (see zika vaccine AIM2021 in dropbox, or doi:10.7326/M20-5306) 

 

Details: 

-- phase I randomized double-blind placebo-controlled clinical study with 100 healthy young adult volunteers for an adenovirus-vector vaccine (Ad26.ZIKV.001), a replication-incompetent human serotype 26 adenovirus vector encoding the Zika membrane (M) and Env proteins, in a 1- or 2-dose regimen of low and high dose (5x10¹⁰ or 1x10¹¹ ) viral particles (LD or HD) 

-- median age 29, BMI 26, 55% female, 72% white/20% Black 

-- study done at the Johnson County Clin-Trials in Kansas and the Beth Israel Deaconess Medical Center in Boston 

-- participants were randomized to one of 5 groups for 2 injections: LD/LD, LD/PL (placebo, 0.9% saline), HD/HD, HD/PL, PL/PL on day 1 and day 57 

-- 86 completed the study 

-- ZIKV (zika virus) neutralizing antibodies were measured at baseline and on days 15, 29, 57, 71, 85, 239, and 365 

    -- seropositivity was considered to be a titer of 10 or higher in the microneutralization assays; this is the threshold titer that provides a protection for licensed flavivirus vaccines. Flaviviruses are arboviruses transmitted to vertebrate hosts by a vector arthropod (ticks and mosquitoes), and also include dengue, yellow fever, Japanese encephalitis, and West Nile viruses

-- 25 participants (all at BIDMC) had the ZIKV-specific T-cell responses measured 

-- vaccine-associated protectivity was determined by transferring purified IgG from the study participants vs a negative control into a non-lethal mouse ZIKV model

-- endpoints: 

    -- primary endpoints: safety and reactogenicity of each regimen (adverse events) for 28 days after vaccination, local and systemic reactogenicity for 7 days after each vaccination, and serious adverse effects immediately reportable 

    -- secondary endpoint: humoral immune response to Ad26.ZIKV.001 by ZIKV serum neutralizing antibody titers 

    -- exploratory endpoints: humoral and cellular (eg T-cell) immune responses elicited by Ad26.ZIKV.001 and protective efficacy by transfer studies to mice 

 

Results: 

-- primary endpoint: safety and reactogenicity: 

    -- most common were injection site pain or tenderness (about 60%), fatigue (30-40%), and headache (about 30%). about 20% had induration/swelling, nausea, myalgia, and chills

    -- after 1^st vaccination: local adverse events (AEs) reported in 75% on the LD groups, 88% in the HD groups, and 45% in the placebo group 

        -- 7 people reported grade 3 solicited systemic events (ie, these were not necessarily spontaneously reported, but were after specific questioning which would likely increase reporting)

    -- after the 2^nd vaccination: local AEs reported in 68% in the LD groups, 78% in the HD groups, and 17% in the placebo group. None exceeded grade 2 intensity 

-- secondary endpoint: vaccine immunogenicity by ZIKV neutralizing antibodies: 

    -- 28 days after the 1^st vaccination: more than 90% seroconverted (88% in LD groups and 94% in the HD groups)

    -- all in the HD/PL group (ie only one shot of the high dose vaccine) seroconverted 56 days after vaccination, with Geometric Mean Titers (GMTs) of 103 (53-203) 

    -- 14 days after the 2^nd vaccination (day 71) the microneutralization assay (MN50) titer peaked in both 2 dose groups with GMTs of 823 (414-1637) in the LD/LD group and 962 (553-1673) in the HD/HD group 

    -- on day 365, the HD/PL group still had detectable MN50 titers with GMTs of 90 (38-212), though this was lower in the LD/PL group where 56% were seropositive with GMTs of 23 (10-4) 

        -- MN50 titers persisted in about 80% of the patients with GMTs of 69 (26-179) for LD/LD and 87 (29-259) for HD/HD 

    -- females had higher MN50 titers at days 57 and 85, as found in other adenovirus-based vaccine studies 

-- exploratory endpoint: IgG antibody transfer study to mice from human participants: 

    -- 6 mg of IgG from vaccinees conferred complete protection from viremia in most recipient animals with statistically significant decreased breakthrough rates and cumulative viral loads per group, as compared to placebo 

    -- 1 mg of IgG conferred partial protection 

    -- pre-challenge MN50 GMTs were higher in protected vs unprotected animals (GMT 16 vs 6) 

    -- and, 30% of the challenged mice were protected in the absence of quantifiable transferred MN50 titers (suggesting that these neutralizing antibodies do not reflect the broader protective immunologic response, or that the measured MN50 titers themselves may not reflect their own efficacy) 

     --T-cell responses were predominantly CD8+, though no M-specific ones were detected

 

Commentary: 

-- there have been >10 candidate Zika virus vaccines assessed to date 

-- neutralizing antibodies have been identified as a correlate of protection in mice and nonhuman primates 

-- this study found that the vaccinations were well-tolerated without any significant safety issues, had potent MN50 titers developed after a single lower or higher dose of Ad26.ZIKV.001 (a 2^nd dose did increase titers, however), and the responses were durable for at least a year for all of the regimens (though with lower titers in those getting the single LD regimen) 

    -- of note, the single HD regimen did fine, did not have significantly more adverse effects, and may be particularly useful for rapid vaccination at the time of outbreaks, in resource-limited settings, or potentially for protection during pregnancy 

-- adenovirus vectors are particularly useful for inducing T-cell responses, including adequate CD4+ T-cells, which do not seem to be attainable with the DNA or the ZPIV (Zika-purified inactivated virus) vaccines 

 

Limitations: 

-- the main limitation is that this is basically a laboratory finding, not a clinical human trial, and laboratory findings do not necessarily translate into human benefit

    -- This is a huge limitation; and given that there aren’t many outbreaks of Zika anymore, this limits the ability to do a viable clinical trial now

-- This was a small study with a limited number of participants who were all quite healthy and young, limiting generalizability to the larger population

-- this population also did not have people from endemic flavivirus regions, and responses in those with antibodies to flaviviruses may be quite different. Also, it is possible that people having had prior infections with this adenovirus could have a blocked or muted response to the vaccine, which also needs to be assessed 

-- one of the huge issues with Zika virus infection in the past was maternal-fetal transmission, congenital neurodevelopmental defects (congenital Zika syndrome, CZS, which had more than 3700 cases in the Americas alone), and neurodevelopmental abnormalities in babies born without symptoms. which means we need info on how pregnant women and the fetuses are likely protected

-- and, though Zika does not seem to be a concern right now, the Aedes aegypti mosquito has been globally expanding its domain (thanks to climate change) and into areas of the world with low levels of immunity to Zika. Which does suggest that Zika may return… 

 

So, a few comments: 

-- unlike with SARS-CoV-2 vaccine development, this Zika vaccine is anticipatory: it is great to have a potentially very potent vaccine available prior to an epidemic/pandemic… 

-- the vaccine is quite impressive in both the level and duration of the response, as well as the protective clinical benefit in mice (though arguably most of us are not mice, and translation of data from across species is a bit fraught)
-- it is likely reasonable that protecting pregnant women from Zika (along with transfer of IgG across the placenta to the fetus) will dramatically decrease the bad viral effects on fetuses and young children 

for the array of prior blogs on zika, see http://gmodestmedblogs.blogspot.com/search?q=zika 

geoff

 

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