covid: a new T-cell vaccine in the works

 A new T-cell vaccine is in the early stages of development but might be a big leap forward in really dealing with our covid-19 scourge (see covid Tcell vaccine nature2022 in dropbox, or doi.org/10.1038/s41586-021-04232-5) 

 

Details: 

--36 participants received CoVac-1, a peptide-based vaccine composed of SARS-CoV-2 T cell epitopes from various SARS-CoV-2 proteins (spike, nucleocapsid, membrane, envelope, open reading frame 8), combined with the Toll-like receptor 1/2 agonist XS15, which has been shown to elicit profound T-cell immunity against SARS-CoV-2 

-- divided into 2 groups: age 18-55yo and 56-80yo 

-- median age 60, 44% female, 100% white, BMI 24 

--pre-existing conditions: hypertension 17%, previous malignancy and mild psoriasis 3% (1 person for each) 

--none had pre-existing SARS-CoV-2 T-cell responses 

--open-label phase 1 trial: 

    -- primary outcome: safety from day 28 (from diary cards) until day 56 (safety visits) 

    -- T-cell response on days 7, 14, 28, 56 and at 3 months, after a single CoVac-1 injection, using interferon- γ enzyme linked immunospot (ELISPOT) assays

 

Results: 

--safety and reactogenicity: no serious adverse events 

    -- systemic solicited adverse events: 

        -- fatigue in 31%, all mild 

        -- headache in 17%, all mild 

    -- reactogenicity:  

        -- 100% had mild to moderate induration (all had the expected granuloma/induration at the injection site, which persisted beyond day 56) 

        -- swelling in 81%, though 6% had severe swelling (all severe effects resolved within 2 days) 

        -- erythema in 92%, 18% severe 

 

-- T-cell responses: 

    -- 100% had vaccine-induced T-cell responses 

        --for those 18-55yo: increase from 0 to 236 spots/500K cells at day 14 to 450 at day 28 

        --56-80yo: increase from 0 to 53 at day 14 to 325 at day 28 

    -- CoVac-1-inducted T cell responses were found for all of the different peptide targets and existed at the 3-month followup 

    -- CoVac-1-induced CD4 T-cell response was up to 40 times higher vs that from SARS-CoV-2 infection, with no difference between the younger and older groups 

    -- CD8 responses were detected in 80% of those 18-55yo and 100% of those 56-80yo 

 

-- variants of concern (VOC) alpha, beta, gamma and delta: 

    --overall 50% of vaccine peptides were not affected by any variant-defining mutations 

        -- and, none of the mutations in the gamma or delta variants affected the CoVac-1 peptides 

    --T-cell responses (CD4 and CD8) to the peptide pools of alpha and beta were detectable in 100% of all age groups, though a few of the responses were lower than those of the original wild-type virus 

        -- however, this response to the overall peptide pool for the alpha and beta variants was at least 10-fold higher than the T-cell response to the wild-type virus   

 

-- the vaccine-induced interferon-γ cell responses persisted in followup at 3 months and was greater than found by either natural infection or by the current vaccines   

 

Commentary: 

-- effective immune response to SARS-CoV-2 infection requires enabling the different components of the immune system, given the need for their intricate, integrated response to the viral infection (eg, see http://gmodestmedblogs.blogspot.com/2022/01/covid-early-treatment-regimens-work.html ). 

 

-- CoVac-1 is a multiple peptide-based vaccine designed as a single injection to elicit long-lasting protection against SARS-CoV-2, with immunity similar to that from natural infection, and this protection should not be affected by current or new VOCs:

    -- in this study, the memory T-cell response to CoVac-1 after the single vaccination had higher responses than from Covid-19 disease or the spike-specific T-cell responses from the mRNA vaccines. These T-cell responses was not affected by the VOCs tested in this study, though some of the VOCs had displayed decreased neutralizing activity after either the Covid-19 disease or the current vaccines 

    -- the T-cell response by this vaccine is dramatically more so than by natural infection. We do not know exactly what the cutpoint of T-cell response that provides long-term protection, but it is clear that long-term protection is variable (eg, much less in those with significant immunologic deficiencies or medications that impair immunologic response), necessitating the booster vaccines

    -- the multiple targets of CoVac-1 are likely to extend the T-cell responsiveness to the omicron variant (not tested) as well as newer variants likely to emerge, thereby being much more effective than our current spike-specific mRNA vaccines, for example

    -- in this study the T-cell response was robust for three months after vaccination, in line with previous experience with other similarly adjuvanted vaccines as well as with old infections (of note, there was significant T-cell persistence 17 years after the original SARS-CoV-1)

    -- the T-cell responses found with CoVac-1 were beneficial: there was induction of the Th1 CD4, as well as reinforcement of CD8 memory T cells

    -- T-cell responses in some cases may be detectable after SARS-CoV-2 exposure without any circulating antibodies detected; in this small study, this was associated with very mild disease (ie, having detectable neutralizing antibodies early may not be necessary to prevent significant disease) see https://wwwnc.cdc.gov/eid/article/27/1/20-3611_article . [ie, assessing just neutralizing antibodies is probably insufficient to quantify the overall effective immune response]

 

-- there was an interesting article 2 years ago suggesting that about 3-15% of individuals not exposed to SARS-CoV-2 had persistent antibodies from likely prior coronavirus infections, especially in children (presumably from exposure to the 4 recurrent seasonal mild infections from coronaviruses) and the less intense disease that kids have from covid-19 might at least partially be explained by the presence of these cross-reactive antibodies (see https://www.science.org/doi/10.1126/science.abe1107 or DOI: 10.1126/science.abe1107)

 

-- in sum, this CoVac-1 study was safe and found to elicit profound, broad and VOC-independent T-cell responses, suggesting potentially major benefit for current and perhaps future VOCs (which needs to be tested in a phase 2 clinical trial; there is one ongoing evaluation for patients with B cell/antibody deficiency

 

--there will be ongoing followup of safety and immunogenicity data until month 6

 

 

Limitations:

-- small sample size of a pretty healthy group limiting generalizability of their results overall (would need a large group with geographical variety, comorbidities, and different  sociodemographics to be more generalizable)

-- the study predated omicron, so not sure that the T-cell response would be as good as they expected.

-- the robustness of the immune response is impressive, but we don’t really know how to interpret it fully. What is the cutpoint of the T-cell responses that is necessary to translate into clinical benefit? Increasing the T-cell response 10-fold or 40-fold, as above, is impressive, but if the lower response is clinically sufficient, then these increases may not translate into anything important.

    -- this study did not have clinical outcome data from this vaccine, which is necessary to assess vaccine efficacy. Bigger clinical studies are necessary to elucidate this, though the results of this study are encouraging. A phase 2 study is ongoing in patients with B-cell defects, including those with cancer on B-cell depleting therapy and other immunoglobulin deficiency syndromes. Of course, a study needs to be done assessing clinical outcomes in the general population

 

So, I bring up this article because we seem to be at a SARS-CoV-2 crossroads: new variants keep popping up, covid-fatigue is everywhere, and it seems we are heading into a long-term endemic covid presence. a few points:

-- the current vaccines are not working as well with omicron and may continue to work less well with subsequent variants (which, of course, could be much worse clinically than omicron)

    -- there was very little protection in those with more remote vaccination, much restored by a booster vaccine, but still less than for prior variants (see http://gmodestmedblogs.blogspot.com/2021/12/covid-omicron-studies-finally-and.html )

    -- a recent press released from Israel suggested that further boostering did not add much (see https://healthpolicy-watch.news/israel-fourth-covid-booster-ineffective/ ), though I am unable to find the full data on this

-- I believe that part of the problem is that our current vaccines are outdated. They were based on the “wild-type” original virus that has mutated lots (and much more so with omicron). To be more effective new vaccines will need to use the omicron or some recent variant as the template, to improve the match with upcoming variants

-- but this type of T-cell vaccine (if it works clinically) is potentially a real breakthrough: it involves many peptides (not just the unifocal spike protein for our current mRNA vaccines) making resistance much less likely to develop. Whenever there is a single vaccine target, effective mutations are more likely to develop in that area (the evolutionary pressure of the vaccine on the virus will preferentially select for variants that escape vaccine coverage)

--and, perhaps there is even benefit from a combination of vaccines: the mRNA vaccines are so phenomenal in protection against older SARS-CoV-2 variants, so perhaps a newly-developed mRNA vaccine with a T-cell stimulant vaccine as above, might be a great combo….

geoff

 

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