COVID: nanoparticle vaccine shows promise

 Another type of vaccine has found very positive results, with high levels of neutralizing antibody to SARS-CoV-2, in a drug company sponsored trial (see covid vaccine nanoparticle NEJM2020  in dropbox, or DOI: 10.1056/NEJMoa2026920) 

 

 Details: 

-- the vaccine (NVX-CoV2373) is a recombinant nanoparticle vaccine composed of trimeric full-length wild type SARS-CoV-2 spike glycoproteins (including the transmembrane domain) and Matrix-M1 adjuvant 

-- 131 healthy adults were randomized to 2 different doses of the vaccine (5 µg and 25 µg), with and without the Matrix-M1 adjuvant, in May 2020 

    -- 83 received the vaccine with adjuvant, 25 without, and 23 placebo 

    -- all were healthy adults <60 years old 

    -- median age 30, 50% female, 79% white, BMI 25 

-- phase 1 trial included 2 injections 21 days apart 

-- primary outcomes were reactogenicity for 48 hours (per the FDA toxicity grading scale), laboratory values to assess safety (per the FDA toxicity scoring), and IgG anti-spike protein response 

-- secondary outcomes included unsolicited adverse events, wild-type virus neutralization (microneutralization assay), and T-cell responses 

    -- safety outcomes were measured as 7 days and 28 days after vaccination

    -- the IgG and microneutralization assay results were compared to those of convalescent serums from 32 patients who had Covid-19

-- participants also had SARS-CoV-2 testing by nasopharyngeal swabs on day 35, or earlier if there were symptoms consistent with infection

 

Results: 

-- reactogenicity was absent or mild in the majority of participants, more common with those receiving adjuvant (2 patients had more severe adverse events of fatigue, headache, and malaise), for a mean of <3 days.

-- Only one patient had a mild fever that lasted one day

-- unsolicited adverse events were mild in most participants (one patient had a mild cellulitis with the 1^st dose and declined the 2^nd dose)

-- no serious adverse events were noted

-- no significant changes in laboratory values were found

 

-- immunologic response at 35 days:

    -- 2-dose 5 µg adjuvanted regimen induced a geometric mean anti-spike IgG (63,160 ELISA units) and neutralization (3906) responses that exceeded the geometric mean response in convalescent serum from Covid-19 patients (8344 and 983, respectively)

        -- by day 21, and prior to the 2^nd vaccination, the geometric mean ELISA unit response was about 2500 units; this increased 8-fold by the 2^nd vaccination

        -- the adjuvant increased the ELISA units by 100-fold

    -- the responses to the 2-dose 5 µg and 25 µg adjuvanted vaccine regimens was similar

-- neutralizing antibody levels:

    -- adjuvanted vaccine led to a fivefold increased geometric mean fold rise after the 1^st vaccination, and 100 times greater than with a single vaccination on day 35 after the 2^nd vaccination

    -- when compared to convalescent serum, the 2^nd vaccination was approximately 4 times greater than those who were symptomatic outpatients and similar to those who were hospitalized with severe Covid-19

-- there was a strong correlation between neutralizing antibody titers and the anti-spike IgG ELISA titers at day 35 (only for the adjuvanted vaccine)

-- T cell response in 16 patients found that only the adjuvanted vaccine induced antigen-specific CD4 responses, targeted to Th1 phenotype with negligible Th2 response

    -- ie, adding the adjuvant resulted in enhanced immune responses, worked well with the low dose vaccine, and these were biased to a more prominent helper T-cell response (Th1)

 

Commentary:

-- this study suggested that safety and immunogenicity of this vaccine was acceptable, with high immune responses and levels of neutralizing antibodies that exceeded the values of symptomatic Covid-19 outpatients and were of the magnitude seen in convalescent serum of those hospitalized with Covid; and the benefits of the Matrix-M1 adjuvant significantly improved antibody responses with just the 5 µg dosing, with enhanced immune responses, and these were biased to a more prominent helper T-cell response (Th1) [these T-cell responses in other viruses correlate with clinical protection]

-- this, as other vaccines being developed, target the spike glycoprotein, which attaches to the human ACE2 receptors that allow for cellular entry of the virus

-- both rodent and nonhuman primate challenges with this vaccine induced high titers of antibodies against the spike protein, which was shown to block ACE2 receptor binding and neutralized wild type virus, more so than in human convalescent serum, and also induced CD4 and CD8 T cell responses, with Th1 phenotype predominance. The neutralizing antibodies responses in nonhuman primates correlated with clinical protection

-- there were other studies on vaccination using nanoparticle technology for RSV (respiratory syncytial virus), which is similar to SARS-CoV-2 in that both infect cells through a type I fusion protein mechanism. With RSV, the vaccine has been found to be protective, with vaccine-induced neutralizing antibody levels correlating with protection

-- There was also a small study of 330 adults over 60 years old of a nanoparticle influenza vaccine with the Matrix -M adjuvant, finding similar reactogenicity and safety to the high dose trivalent Fluzone, and with significantly greater hemagglutinin inhibition (see https://www.nejm.org/doi/full/10.1056/NEJMc1803554 )

-- one advantage of this vaccine over the mRNA ones being trialed now is that it has a track record for safety: this type of nanoparticle vaccine has been used for RSV vaccines in more than 14,000 participants including children, pregnant women, and in those > 60 years old; as well as with 4300 participants getting the Matrix-M1 adjuvant (for the comparatively very limited data on the safety of mRNA vaccines, see http://gmodestmedblogs.blogspot.com/2020/07/covid-mrna-vaccine-works-in-nonhuman.html ).

 

Limitations:

-- though these immunologic responses are quite impressive, actual human data of efficacy is essential. The fact that this nanoparticle vaccine worked clinically in non-human primates, where the level of wild-type neutralizing antibodies correlated with vaccine production, is also encouraging. As well as the prior human studies on RSV and influenza noted above

-- This was of small trial which limits its generalizability, and there was minimal ethnic diversity. In addition, this was a group of healthy younger people with short follow-up. There will be subsequent safety data presented after 105 days from vaccination

 

so, it is truly impressive that so many vaccines using different methodologies have been developed in such a short period of time, and with several ready for larger clinical trials so quickly. The advantages of the mRNA vaccine have been presented in earlier blogs as per above, including their being relatively easy to develop, easy to tweak, and much faster to manufacture in large quantity and at a low price. And there is no need for an adjuvant, which does increase the adverse effects. The advantage of the nanoparticle vaccine with adjuvant is that it has been used previously with an apparently safe profile and clinical efficacy, especially with the similar RSV vaccine.

 

 Trials are or will be underway for these vaccines to assess their actual clinical efficacy. But it does seem increasingly likely that we actually will have a functional vaccine in the relatively near future

geoff

 

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