Coming vaccines

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(Ella 2021b). Covaxin has also been reported to induce Th1-biased antibody responses with an elevated IgG2a/IgG1 ratio and increased levels of SARSCoV-2-specific IFN-γ + CD4+ T lymphocyte response (Ganneru 2021). On 3 January, the Drugs Controller General of India (DCGI) approved the emergency use of Covaxin, making it India’s first vaccine against the pandemic, even though Phase III safety and efficacy clinical trials had not been completed. At that time, 22,500 of the 25,800 participants in a Phase III trial had been vaccinated (CTRI/2020/11/028976). On 21 April, Bharat Biotech announced that the second interim analysis of the Phase III study demonstrated a 78% vaccine efficacy in mild, moderate, and severe COVID-19 disease and a 70% efficacy against asymptomatic COVID-19 infection (Bharat 20210421). Preliminary results suggest that Covaxin could be effective against B.1.1.7 (Sapkal 2021) and only slightly less effective against B.1.617 (Yadav 2021). These data need to be confirmed. Bharat has yet to publish detailed results of their Phase III trial. As of 2 May, the vaccine has been approved in 14 countries.

Other vaccines

For information about other vaccines, refer to the excellent New York Times collection curated by Carl Zimmer, Jonathan Corum and Sui-Lee Wee: 1. The Coronavirus Vaccine Tracker (Carl Zimmer, Jonathan Corum and Sui-Lee Wee) – Excellent overview of all vaccines in development, always up-to-date. 2. How Nine Covid-19 Vaccines Work (Jonathan Corum and Carl Zimmer) – Almost 100 vaccines are in human trials. Find out how 9 of them work.

The Novavax vaccine

The Novavax vaccine ‘NVX-CoV2373’ is a recombinant “nanoparticle” vaccine (rSARS-CoV-2; sometimes also called a ‘protein9 subunit vaccine’) composed of trimeric full-length SARS-CoV-2 spike glycoproteins and Matrix-M1 adju-

9 Licensed protein-based vaccines include the hepatitis B vaccine licensed in 1986, a flu vaccine approved in 2013 and the human papillomavirus vaccine for the prevention of of cervical cancer.

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vant. The vaccine is produced by creating insect-infecting baculoviruses containing a gene for a modified SARS-CoV-2 spike protein which infects moth cells (the fall armyworm, Spodoptera frugiperda) in 2000 liter bioreactors (Wadman 2020). After extraction and chromatographical purification of the spike proteins, mixing with lipid particles and further co-formulation with the saponin-based adjuvant Matrix-M1 (Bangaru 2020, Tian JH 2021), NVXCoV2373 is stored and stable at 2°-8°C (36°-46°F). An early analysis revealed that the full-length immunogen was locked in a prefusion conformation (Bangaru 2020) and binds with high affinity to the ACE2 receptor. Early preclinical studies in mice and baboons revealed strong B and T cell responses to NVX-CoV2373 with no evidence of vaccineassociated enhanced respiratory disease (VAERS) (Tian JH 2021). In macaques, prime and booster immunization protected against SARS-CoV-2 replication in the nose and lungs, with no detectable replicating virus (sgRNA) in either upper or lower respiratory tracks (Guebre-Xabier 2020). Importantly, the authors of this paper also noted an absence of pulmonary pathology in the vaccinated animals. A small Phase I/II clinical trial (Australia, n = 131) showed that the vaccine induced immune responses that exceeded levels seen in COVID-19 patients (Keech 2020). After the second vaccination neutralizing antibody responses were comparable to those seen in convalescent patients hospitalized with COVID-19. Preliminary results from a Phase III trial in the UK (15,000 adult participants, with 27% percent being older than 65) suggest that the vaccine, administered as two injections 3 weeks apart, might be 96% effective against mild, moderate and severe disease caused by the historical SARS-CoV-2 strain (Novavax 20210311). Against variant SARS-CoV-2 strains, the Novavax vaccine: • Maintains its efficacy more or less against the B.1.1.7 variant (first detected in England): 86.3% (95% CI: 71.3, 93.5) (Novavax 20210311) • Shows 50% to 60% efficacy against the B.1.351 variant (depending on HIV serostatus). In a Phase II trial10 in South Africa where most SARSCoV-2 infections were caused by B.1.351 (Shinde 2021), efficacy was: o 60.1% in HIV–negative participants o 49.4% in HIV-positive participants

10 Among 2684 participants who were SARS-CoV-2-seronegative at baseline (94% of them were HIV-negative and 6% were HIV-positive), symptomatic COVID-19 was observed in 15 participants in the vaccine group and in 29 participants in the placebo group.

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Of interest, in a preliminary efficacy analysis of the South African Phase II trial, the incidence of COVID-19 observed among participants who were SARSCoV-2 seronegative at baseline was 5.3% (33 mild and 47 moderate cases among 1516 vaccinees), similar to the 5.2% incidence among SARS-CoV-2 seropositive vaccinees (14 mild and 21 moderate cases among 674 participants) (Shinde 2021), suggesting that “previous infection with historical viruses did not appear to reduce the risk of COVID-19 after subsequent infection with B.1.351 (Shinde 2021).

Small in vitro studies of serum specimens from vaccinees suggest that B.1.1.7 (the variant first identified in [fii] England) and B.1.429 (fii California) are only slightly less sensitive to neutralization than the historical strain, whereas B.1.351 (fii South Africa) was found to be 9 to 14 times less sensitive (Shen X 2021, Shen X 2021b).

In a Phase II study in South Africa, adverse events generally subsisted within three days. The most common solicited systemic adverse events after both doses were pain at the injection site (more than one third of all vaccinees), headache (20 to 25%), muscle pain (17 to 20%), and fatigue (12 to 16) (Shinde 2021).

The company has also expanded its Phase III trial to include up to 3000 children ages 12 to 17.

Novavax has started a rolling review process of NVX-CoV2373 vaccine candidate with EMA, FDA, MHRA and Health Canada. However, because of regulatory and manufacturing problems, the Novavax vaccine is not expected to be authorized before July 2021 (Thomas 2021), with production reaching a peak only at the end of the year or later. This delay will impact a recent partnership with Gavi to supply 1.1 billion doses of the vaccine to low- and middleincome countries (Novavax 20210506). In April, financial analysts anticipated $33 billion in total sales 2021–2027 (GlobalData 20210408). The discrepancy between this forecast and the paucity of published scientific data is disconcerting.

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The Phase III PREVENT-19 trial (NCT04611802) in the US and Mexico was postponed several times as Novavax struggled to scale up its manufacturing capability. Recently, the company announced that it would not be able to reach the initial production target of 150 million doses a month because of supply shortages including the bags used to grow the moth cells (Reuters 20210413). In 34 years, Novavax has never won regulatory approval for any of a vaccine candidates.

The CureVac vaccine

The CureVac vaccine ‘CVnCOV’ (proposed international non-proprietary name: Zorecimeran) is a lipid nanoparticle-encapsulated mRNA vaccine that encodes full-length, pre-fusion stabilised SARS-CoV-2 spike protein. Preclinical studies showed that the vaccine induced strong humoral responses in Syrian hamsters with high titers of virus-neutralizing antibodies and robust T cell responses. Upon challenge after two vaccinations with 10 µg, the hamsters were protected – there was a significant reduction in replicating virus levels in the upper respiratory tract and no detectable live virus in the lungs (Rauch 2021). In rhesus macaques as well, the vaccine seems to be safe and immunogenic, protecting vaccinated animals (2 x 8 μg four weeks apart) from challenge infection with SARS-CoV-2 (Rauch 2020). Interim results of a clinical Phase I trial showed that among 245 healthy adults 18 to 60 years old, compliance was good – 231 (94%) received their second administration (Kremser 2020). SARS-CoV-2 S protein IgG and virus neutralization test responses were detectable after the first vaccine dose, and all were markedly increased within 7 days of the second dose (Kremser 2020). Local reactions at the injection site were generally mild to moderate, as were systemic adverse events (AEs) such as headache, fatigue (and to a lesser extent myalgia and chills). Severe AEs generally decreased or disappeared rapidly within 24–48 hours. In December 2020, CureVac launched a Phase III trial which was to recruit 36,500 volunteers (NCT04652102, two vaccine doses four weeks apart). The first efficacy data are expected within weeks. The vaccine is stable at least three months at 2–8°C (36–46°F).

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For the clinical development and the manufacturing of its vaccine, CureVac has been announcing a series of collaborations with Bayer (CureVac 20210107), GSK (CureVac 20210203) and Novartis (CureVac 20210304). On 12 February, the European Medicines Agency (EMA) started a rolling review of the vaccine based on preliminary data from pre-clinical data and early clinical studies (EMA 20210212). While results of the ongoing Phase III trial of CVnCoV have still not been published, the company is already working on a sister compound, CV2CoV, a second-generation mRNA vaccine, which increased levels of protein expression in cell culture and induced strong and dose-dependent immune responses in rats already after the first vaccination (Roth 2021). When vaccinated with 0.540µg CV2CoV, the serum of the animals also demonstrated significant crossneutralization against B.1.1.7 (first detected in [fdi] England), B.1.1.298 (fdi Denmark) and B.1.351 (fdi South Africa). As CV2CoV is based on a new mRNA backbone designed to improve intracellular mRNA stability and translation, strong immune responses might be induced with lower doses. The company has a dream: development of multivalent vaccines to target rapidly spreading COVID-19 variants (CureVac 20210513). Lowering doses could also contribute to reduce worldwide vaccine shortages. It is too soon to know if the dream will come true. Clinical trials for CV2CoV are not expected to start before the third quarter of 2021.

It will be interesting to follow a CureVac-Tesla collaboration on developing portable, automated mRNA production units (mRNA “micro-factories”) which – if successfully deployed around the world – could produce billions of doses of vaccine (Reuters 20200702).

The Sanofi/GSK vaccine

The Sanofi/GSK vaccine (also known as VAT00002) is an adjuvanted recombinant protein subunit vaccine. It is produced in insect cells via a baculovirus vector carrying genes that code for the SARS-CoV-2 spike protein. The vaccine uses the same technology Sanofi used for its Flublok influenza vaccine (Dunkle 2017). On 17 May 2021, Sanofi announced that its vaccine had shown 95% to 100% seroconversion rates following a second injection in all age groups (18 to 95 years old). In the Phase II study (n = 722, US and Honduras), the neutralizing antibody levels of the two-dose regimen (given 21 days apart) were comparable to those generated by natural infection (Sanofi 20210715). A Phase III study could start in May/June and produce results by