Mon, 06/07/2021 - 17:26
Dear colleagues,
My starting point this time is a nice comparison between the different vaccines against “wild type and variants of concern (VOC). There is also some news about Sputnik, about Brazil and the upcoming Chinese mRNA vaccine.
Ep 145-1: Shapiro in medRxiv based on published data and media reports on trials and observational clinical studies (hence in vivo data, but not all peer-reviewed!).
- Clinical observation in conditions where wild-type virus was predominant
- Fig 1: vaccine efficacy (VE) against any disease after 2 doses: Moderna = Pfizer > Novavax > Astra-Zeneca > Sinopharm (BBIBP-CorV) > Sinovac (Coronavac):
- Taking into account the confidence intervals (CI) the protein Novavax approaches the mRNA and inactivated Sinopharm is equivalent to AZ!
- The Russian Ad26/Ad5 is not mentioned here, but has reported a VE similar to the mRNA vaccines of over 90 %
- Fig 2: VE WT any disease after 1 dose: remarkably: J&J is not more active than AZ !
- Fig 3-5: VE against severe disease, hospitalization and death: most are (very) efficient, even after 1 dose, but sometimes very wide CI.
- Fig 7: VE against infection: Moderna and Pfizer 90 % and AZ 77 %, but overlapping
- Fig 8: VE against infectiousness/transmission:
Pfizer 90 % > Moderna 80 % > J&J 65 % > AZ 50%
- Clinical observations on variants of concern (VOC) :
- British B.1.1.7 (alpha): Pfizer, Moderna and AZ almost equal activity as against WT
- South-African B.1.351 (beta): Pfizer 75% > J&J and Novavax 50% > AZ 22 %
- Brazilian P.1 (gamma): J&J 66% > Sinovac 50%
Ep 145-2: Ikegama investigates the in vitro neutralizing capacity of sera from subjects vaccinated with Sputnik V (Ad26/Ad5) against VOC, showing that activity against B.1.1.7 (alpha) is similar as WT, but strongly (6 X) reduced against B.1.315 (beta) and moderately (3 X) against P.1 (gamma).
Table 2 p.16 provides an overview of in vitro studies with sera from recipients of vaccines. The same trends are evident: alpha remains rather sensitive and beta is most resistant, but data are very hard to compare, because these assays are not standardized and also the timing and other characteristics of the serum donors are most probably different. See for instance the large differences between average resistance of the beta VOC by sera from Pfizer recipients in different studies: from less than 6.5 to 35 times.
Ep 145-3: is the bad news from Brazil: the explosive epidemic with “gamma”. 3 A is a journalist summary, 3 B is the nice paper in Nature
Summary:
- Lineage replacements were a recurrent phenomenon in the local evolution of SARS-CoV-2 in Amazonas state, driven by ecological and virological factors.
- Non-pharmacological interventions (NPI) in Amazonas state in April 2020 were sufficiently effective to reduce the Re of early prevalent local SARS-CoV-2 clades but were insufficient to keep the epidemic under control, allowing the … emergence of the VOC P.1 in late November/early December 2020.
- The lack of efficient social distancing and other NPI mitigation measures probably allowed a sudden and accelerated transmission of VOC P.1. At the same time, the higher transmissibility of this VOC further fueled the rapid upsurge in SARS-CoV-2 cases and hospitalizations observed in Manaus following its emergence.
- NPIs implemented in Manaus since early January 2021 effectively reduced the median Re of the VOC P.1 by approximately 50%.
Therefore, our results suggest that weak adoption of NPIs represents a risk for the continuous emergence of new variants.
Implementation of efficient mitigation measures, combined with widespread vaccination, will be crucial to controlling the spread of SARS-CoV-2 VOCs in Brazil.
Ep 145-4: is the good news from Brazil: in A, Sofia Moutinho, a Brazilian Science journalist describes how the rather small town of Serrana is an almost COVID-free oasis (80 % drop in cases and 95 % drop in deaths, after inhabitants had been massively vaccinated with Coronavac, the inactivated vaccine from the Chinese Sinovac-Butantan Co..
In B, a Brazilian phase 3 trial with this vaccine is described. It was conducted between July and Dec 2020, when SARS-CoV-2 B.1.1.28 was prevalent, hence before P1 and P2 (gamma) were predominant. CoronaVac has an overall efficacy of 50 % against any symptomatic disease, but a much higher efficacy (83-100 %) for increasingly severe disease.
Neutralization assays (not described in detail) showed that the elicited antibodies were equally potent to neutralize the P1/P2 variants as compared to the B.1.1.28.
Although both reports are not peer-reviewed, they suggest that a moderately active inactivated vaccine is able to very efficiently curb the epidemic, even with a E484K containing variant.
Therefore, the conclusion from C “WHO approval of CoronaVac may be crucial….” seems justified.
Ep 145-5: the upcoming Chinese mRNA vaccine SW0123 (StemiRNA Co.)
In A (peer-reviewed) the vaccine is presented and tested pre-clinically: it is a full-length “native” Spike mRNA, bound tightly to a positively charged cationic compound (SW-01) to form a dense core structure that is encapsulated in a PEG-lipid shell, thus forming a “core shell” lipid nanoparticle, resembling a virus that will also trigger Toll-like receptors and taken up by antigen-presenting cells (see Figure 1 p. 2). In this paper, immunogenicity in mice and non-human primates is shown: both neutralizing antibodies and Th1 responses (see Fig 3 and 4). Also protection against SARS-CoV-2 infection and lung disease (see Fig 5 and 6). The claim of neutralization against variants seems based on activity against single-mutant viruses (Fig 3e).
In B (non-peer reviewed) a very small study in two human volunteers, who were “primed” with two doses of an inactivated vaccine from the Chinese Academy of Clinician Sciences (still under phase 3 trial) were “boosted” 7 months later with one dose of this mRNA vaccine. There was a strong increase in antibodies (including neut rising slightly above the level of convalescent sera), S-specific memory B cells (Fig 1) and Th1 responses. (Fig. 2).
Ep 145-6: The CVnCoV mRNA candidate CureVac. This German company has published peer-reviewed preclinical data (A) and non-peer reviewed phase 1 data (B). In the meantime, phase 2/3 trials are ongoing (C)
A: The CureVac mRNA is very similar to the Pfizer and Moderna “S-2P”: S protein with intact S1/S2 cleavage site and transmembrane domain, as well as K986P and V987P mutations and it is also formulated in a lipid nanoparticle from Acuitas. (Hence slightly different from the Chinese mRNA, using unmodified “native S and a different core shell LLP). It induces high neutralizing antibodies and Th1 responses in mice, with both CD4 and CD8 T cells, expressing IFN-g and TNF-a, as well as an induction of type 1 IFN. There is a clear protection against SARS-CoV-2 by two doses in hamsters.
B: As could be expected from Pfizer and Moderna trials, dose-dependent mild to moderate local and systemic reactions are rather frequent, but no serious side effect was observed and side effects were less after the second dose. Two doses of 12 µg induced neutralizing titerts similar (but not clearly higher) than convalescent sera.
C: https://finance.yahoo.com/news/curevac-cvac-announces-positive-data-211409487.html
Ep 145-7: A very nice and thorough review on “all you wanted to know” about mutants….
My conclusions:
- Even “weaker” vaccines (such as the Adeno and inactivated ones) remain very useful to contain the epidemic, even for the alpha (British) and gamma (Brazilian) VOC, but Astra-Zeneca essentially failed against beta (South-African).
- A Chinese mRNA, SW0123 (StemiRNA Co.), slightly different from Pfizer and Moderna, is in an advanced stage. NHP data suggest that it may be protective. Early clinical evidence suggest that it could also used as a boost for the inactivated vaccines (known to induce less potent T cell responses).
- The German CVnCoV mRNA candidate CureVac, very similar to Pfizer and Moderna, has presented preclinical and phase 1 data and is now progressing in phase 3.
Best wishes,
Guido
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