COVID: potential new vaccine; and environmental disruption leads to zoonotic infections

A trial of a novel SARS-CoV-2 vaccine in Wuhan found that it was tolerable and quite immunogenic (see covid vaccine adenovir lancet2020 in dropbox, or https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(20)31208-3.pdf)

 

Details:

-- the vaccine, developed in China, involves a recombinant adenovirus type-5 (Ad-5) vectored Covid-19 vaccine expressing the spike glycoprotein of the SARS-CoV-2 virus

-- 108 participants were randomized to a dose escalation, single center, open-label, nonrandomized, phase 1 trial in Wuhan, between March 16 and March 27

    -- all patients stayed in a designated hotel for 14 days postvaccination, to decrease the likelihood of exposure to SARS-CoV-2 during the early stages postvaccination

-- patients were 18-60 years old, and allocated to a low, medium, and high dose vaccine, given once intramuscularly. All had negative results of several SARS-CoV-2 tests: serum specific IgG and IgM antibodies, negative PCR in pharyngeal swabs, or sputum and anal swabs, and a clear chest CT

-- mean age 36, 50% male, underlying disease 7% (hypertension, chronic bronchitis, gout, hepatitis B carrier)

-- primary outcome: adverse events in the 7 days postvaccination, and safety at 28 days. Specific SARS-CoV-2 antibodies were measured with ELISA, and neutralizing antibody responses were assessed; also specific T cell responses were assessed by enzyme-linked immunospot (ELISpot) and flow-cytometry analyses

 

Results:

-- adverse effects: at least one within the 1^st 7 days in 80% of people, overall evenly found amongst the different vaccine potency groups, with 9% having a grade 3 adverse event (17% in the high dose group, 6% and the other 2)

    -- most common was injection site pain (54%); most common systemic adverse reactions were fever (46%), fatigue (44%), headache (39%), and muscle pain (17%). Grade 3 fever (axillary temperature> 38.5°C) was present in 8% overall, 6% in the low and middle those groups. These reactions occurred within 24 hours after vaccination and persisted for no more than 48 hours. The grade 3 events were more common in the high dose group. There was also mild elevations of the ALT, blood sugar, and bilirubin, but none of these were considered clinically significant

    -- most of these reactions were mild to moderate in severity. No serious adverse events occurred within 28 days postvaccination

 

-- Antibody responses:

    -- ELISA antibodies to the receptor binding domain (RBD) of SARS-CoV-2, with at least 4-fold increase:

        -- day 14: 50%

        -- day 28: 97%

    -- neutralizing antibodies to live SARS-CoV-2 virus:

        -- day 14: 35%

        -- day 28: 60%
        -- those with pre-existing high titers of Ad-5 neutralizing antibodies had a lower likelihood of seroconversion of neutralizing antibody postvaccination to SARS-CoV-2. And the older age group (45-60yo) had a lower seroconversion of neutralizing antibodies [though this was a small group in the study]

 --ELISpot responses were undetectable in all participants at baseline but peaked at 14 days postvaccination with >90% responding, moreso in the middle and high dose groups; there was minimal decrease at 28 days. 

    --High levels of baseline Ad-5 neutralizing antibody titer reduced the peak of postvaccination T cell responses in all vaccination groups, especially in the low dose group. However despite the effect of high pre-existing Ad5 immunity, positive responses were still identified in 95% of the middle and high dose groups at day 14 and about 90% at day 28

-- interferon gamma was detected from the CD4 and CD8 T-cells after vaccination at days 14 and 28 in all vaccination groups, though higher in the middle and high dose groups. Similarly with the TNF-a expression from CD8-T cells

Commentary:

-- there has been some evidence that adenovirus-vectored vaccines may be helpful, for example finding with ebola virus in non-human primates an apparent protective immunity in challenge studies at 48 weeks (see Ledgerwood JE. N Engl J Med 2017; 376: 928-38)

-- it is pretty clear currently that the real hope for ending our current Covid-19 pandemic is to develop an effective vaccine against SARS-CoV-2 (especially as the virus seems to be peaking again pretty shortly after states/countries have relaxed social isolation and travel restrictions)

-- there are 130 vaccines being developed, and at least 8 have started or will soon start clinical trials

-- and, a preclinical study in ferrets found that 7 of 8 were protected from having detectable virus when challenged with SARS-CoV-2 twenty-one days after immunization with this vaccine

-- this study did find rapid detection of immunologic response, by day 14, after a single dose of the vaccine

-- there was broad-based immunologic response, including humoral and T cell responses; at 28 days postvaccination, over 90% of those in the middle and high dose groups had positive T cell responses to spike glycoprotein and ELISA antibodies to SARS-CoV-2 virus, and 60% had neutralizing antibodies to live virus 

-- studies from SARS and MERS suggested that specific antibody responses were temporary and declined quickly after recovery, but T-cell responses seemed to play an essential role in longer-term immunity. There was a rapid decline of specific antibody response in SARS-CoV-2 in prior studies. the apparent persistence of T-cell responses to this vaccine, even with those having pre-existng neutralizing antibodies to Ad-5, is therefore hopeful. But, it is difficult to extrapolate actual clinical immunity based just on laboratory assessments as in this study (ie, we really need larger RCTs with diverse populations and ages).

-- though Ad-5 immunity had less of a response to their vaccine (esp neutralizing antibodies), with other adenovirus-vectored vaccines in prior studies there were methods to boost these responses.

-- for prior blogs on the development of SARS-CoV-2 vaccines, see http://gmodestmedblogs.blogspot.com/search?q=covid+vaccine

Limitations of the study: 

-- small sample size with short follow-up, though they will continue to follow this cohort for at least 6 months

-- limited numbers of participants older than 50. though they intend to extend the study to older people in phase 2 of the study

-- only evidence of laboratory-based immunologic response, not actual clinical effectiveness

-- and there is some concern about the increased risk of HIV-1 acquisition associated with Ad-5 activated CD4 cells (ie, immunologic manipulations may have unexpected consequences: we need to be alert to potential collateral damage)

so, vaccines are (by far) the most likely path out of the Covid-19 pandemic. it is reassuring that there are 130+ vaccines in development, and some seem to be pretty quickly scalable to large populations (eg see http://gmodestmedblogs.blogspot.com/2020/06/covid-readers-comments-retracted.html ). i do hope that there is some national and international coordination of vaccine development, to allow for combinations of vaccines (eg, as with development multi-epitope vaccines) that might improve effectiveness, and that the draw of potentially huge profits by individual companies does not undercut rapid effective vaccine development

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as a related SARS-CoV-2 issue: there was an impressive editorial in the NY Times today suggesting that human geographical expansion, decreased animal biodiversity, and consumption of wild animals set the stage for recent, current, and future severe zoonotic outbreaks: https://www.nytimes.com/2020/06/17/magazine/animal-disease-covid.html?referringSource=articleShare

geoff

 

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