Novavax trials in SA and UK confirm high efficacy against original and variants

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Results of the Novavax COVID-19 vaccine trial in South Africa and UK have confirmed high levels of efficacy against the original and variant COVID-19. The results show 100% protection against severe disease in both the South Africa and the UK trials. Results also showed efficacy against variants circulating in South Africa and the UK.

An updated analysis of the Novavax vaccine trial in South Africa shows vaccine efficacy of 55.4% against mainly mild COVID-19 among HIV-negative trial participants, in a country where the vast majority of strains are B.1.351 escape variants. In addition, protection against severe disease due to the B.1.351 variant dominating in South Africa was 100%, with all COVID-19 hospitalisation and deaths having occurred in the placebo group.

Professor Shabir Madhi, executive director of the Wits Vaccines and Infectious Diseases Analytics (VIDA) Research Unit, leads the Novavax COVID-19 vaccine trial in South Africa.

“The results from the South African trial reinforce that, even with the evolution of the SARS-CoV-2 virus developing mutations in an attempt to evade immune responses induced following natural infection by ancestry virus, the first generation of COVID-19 vaccines still offer great potential especially in mitigating severe disease and death from COVID-19.

This was evident in South Africa where all the cases of COVID-19 hospitalisation and death occurred in the unvaccinated control group. This despite the effectiveness of the first generation COVID-19 vaccines being variably affected in reducing the risk of mild COVID-19 caused by the B.1.351 variant, due to the variant being relatively resistant to the antibody induced by all Covid-19 vaccines.”

In a separate study of the Novavax COVID-19 vaccine in the UK, efficacy was 96.4% against the original virus strain and 86.3% against the B.1.1.7/501Y.V1 variant circulating in the UK (post hoc).

These updated final analyses build on the successful interim results announced in January 2021, adding substantially more COVID-19 cases and statistical power in both studies.

In both the South Africa and UK trials, these analyses showed that the vaccine is well-tolerated, with low levels of severe, serious and medically attended adverse events at day 35, balanced between vaccine and placebo groups.

The South Africa trial was a randomised, observer-blinded, placebo-controlled Phase 2b clinical trial. One cohort evaluated efficacy, safety and immunogenicity in approximately 2 665 healthy adults. The second cohort evaluated safety and immunogenicity in approximately 240 medically stable, HIV- positive adults.

A complete analysis of vaccine efficacy among 147 PCR-positive cases (51 cases in the vaccine group and 96 in the placebo group) demonstrated an overall efficacy of 48.6% with majority of illness being mild or moderate.

The vast majority of cases during the efficacy analysis were due to the B.1.351/501Y.V2 variant circulating in South Africa. All five cases of severe disease observed in the trial occurred in the placebo group. Among HIV-negative participants, 55.4% efficacy was observed.

The complete analysis shows that vaccine-induced protection began 14 days after dose 1, although increased efficacy was observed seven days after dose 2, the primary endpoint for the study.

A previously reported initial analysis from the study through 60 days indicated that prior infection with the original COVID-19 strain might not completely protect against subsequent infection by the variant predominantly circulating in South Africa.

However, the complete analysis of the South Africa trial indicates that there may be a late protective effect of prior exposure with the original COVID-19 strain. In placebo recipients, at 90 days the illness rate was 7.9% in baseline seronegative individuals, with a rate of 4.4% in baseline seropositive participants.

Madhi says: “As a benefit to the study volunteers, without whose selfless contribution this important study would not have been possible, we now plan to offer all of them the Novavax vaccine so they can be protected immediately against mild – and more importantly – severe COVID-19 being caused by the B.1.351 variant.”

 

Stanley C Erck, president and CEO, Novavax said:
“With today’s results from our UK Phase 3 and South Africa Phase 2b clinical trials, we have now reported data on our COVID-19 vaccine from Phase 1, 2 and 3 trials involving over 20,000 participants. In addition, our PREVENT-19 US and Mexico clinical trial has randomised over 16,000 participants toward our enrolment goal of 30,000. NVX-CoV2373 is the first vaccine to demonstrate not only high clinical efficacy against COVID-19 but also significant clinical efficacy against both the rapidly emerging UK and South Africa variants. NVX-CoV2373 has the potential to play an important role in solving this global public health crisis. We look forward to continuing to work with our partners, collaborators, investigators and regulators around the world to make the vaccine available as quickly as possible.”

NVX-CoV2373 contains a full-length, prefusion spike protein made using Novavax’ recombinant nanoparticle technology and the company’s proprietary saponin-based Matrix-M™ adjuvant. The purified protein is encoded by the genetic sequence of the SARS-CoV-2 spike (S) protein and is produced in insect cells. It can neither cause COVID-19 nor can it replicate, is stable at 2°C to 8°C (refrigerated) and is shipped in a ready-to-use liquid formulation that permits distribution using existing vaccine supply chain channels.

UK Phase 3 results: 89.3% efficacy
The study enrolled more than 15,000 participants between 18-84 years of age, including 27% over the age of 65. The primary endpoint of the UK Phase 3 clinical trial is based on the first occurrence of PCR-confirmed symptomatic (mild, moderate or severe) COVID-19 with onset at least 7 days after the second study vaccination in serologically negative (to SARS-CoV-2) adult participants at baseline.

The first interim analysis is based on 62 cases, of which 56 cases of COVID-19 were observed in the placebo group versus 6 cases observed in the NVX-CoV2373 group, resulting in a point estimate of vaccine efficacy of 89.3% (95% CI: 75.2 – 95.4). Of the 62 cases, 61 were mild or moderate, and 1 was severe (in placebo group).

Preliminary analysis indicates that the UK variant strain that was increasingly prevalent was detected in over 50% of the PCR-confirmed symptomatic cases (32 UK variant, 24 non-variant, 6 unknown). Based on PCR performed on strains from 56 of the 62 cases, efficacy by strain was calculated to be 95.6% against the original COVID-19 strain and 85.6% against the UK variant strain [post hoc].

The interim analysis included a preliminary review of the safety database, which showed that severe, serious, and medically attended adverse events occurred at low levels and were balanced between vaccine and placebo groups.

“These are spectacular results, and we are very pleased to have helped Novavax with the development of this vaccine. The efficacy shown against the emerging variants is also extremely encouraging. This is an incredible achievement that will ensure we can protect individuals in the UK and the rest of the world from this virus,” said Clive Dix, chair, UK Vaccine Taskforce.

Novavax expects to share further details of the UK trial results as additional data become available. Additional analysis on both trials is ongoing and will be shared via prepublication servers as well as submitted to a peer-reviewed journal for publication. The company initiated a rolling submission to the UK’s regulatory agency, the MHRA, in mid-January.

South Africa results: Approximately 90% of COVID-19 cases attributed to South Africa escape variant
In the South Africa Phase 2b clinical trial, 60% efficacy (95% CI: 19.9 – 80.1) for the prevention of mild, moderate and severe COVID-19 disease was observed in the 94% of the study population that was HIV-negative. Twenty-nine cases were observed in the placebo group and 15 in the vaccine group. One severe case occurred in the placebo group and all other cases were mild or moderate. The clinical trial also achieved its primary efficacy endpoint in the overall trial population, including HIV-positive and HIV-negative subjects (efficacy of 49.4%; 95% CI: 6.1 – 72.8).

This study enrolled over 4,400 patients beginning in August 2020, with COVID-19 cases counted from September through mid-January. During this time, the triple mutant variant, which contains three critical mutations in the receptor binding domain (RBD) and multiple mutations outside the RBD, was widely circulating in South Africa. Preliminary sequencing data is available for 27 of 44 COVID-19 events; of these, 92.6% (25 out of 27 cases) were the South Africa escape variant.

Importantly in this trial, approximately 1/3 of the patients enrolled (but not included in the primary analyses described above) were seropositive, demonstrating prior COVID-19 infection at baseline. Based on temporal epidemiology data in the region, the pre-trial infections are thought to have been caused by the original COVID-19 strain (non-variant), while the subsequent infections during the study were largely variant virus. These data suggest that prior infection with COVID-19 may not completely protect against subsequent infection by the South Africa escape variant, however, vaccination with NVX-CoV2373 provided significant protection.

“The 60% reduced risk against COVID-19 illness in vaccinated individuals in South Africans underscores the value of this vaccine to prevent illness from the highly worrisome variant currently circulating in South Africa, and which is spreading globally. This is the first COVID-19 vaccine for which we now have objective evidence that it protects against the variant dominating in South Africa,” says Maddi. “I am encouraged to see that Novavax plans to immediately begin clinical development on a vaccine specifically targeted to the variant, which together with the current vaccine is likely to form the cornerstone of the fight against COVID-19.”

Novavax initiated development of new constructs against the emerging strains in early January and expects to select ideal candidates for a booster and/or combination bivalent vaccine for the new strains in the coming days. The company plans to initiate clinical testing of these new vaccines in the second quarter of this year.

“A primary benefit of our adjuvanted platform is that it uses a very small amount of antigen, enabling the rapid creation and large-scale production of combination vaccine candidates that could potentially address multiple circulating strains of COVID-19,” said Dr Gregory M Glenn, president of research and development, Novavax. “Combined with the safety profile that has been observed in our studies to-date with our COVID-19 vaccine, as well as prior studies in influenza, we are optimistic about our ability to rapidly adapt to evolving conditions.”

The Coalition for Epidemic Preparedness Innovations (CEPI) funded the manufacturing of doses of NVX-CoV2373 for this Phase 2b clinical trial, which was supported in part by a $15m grant from the Bill & Melinda Gates Foundation.

 

University of the Witwatersrand material

 

Novavax material

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