Coronavirus (41) Nationwide COVID-19 immunization in Israel

Coronavirus (41) Nationwide COVID-19 immunization in Israel
The nationwide vaccination programmes for COVID-19 have been rolled out in several countries. Surveillance report from the Israel vaccination programme which uses BNT162b2 (by Pfizer and BioNTech, mRNA vaccine) has been published early this month.¹ In contrast with the report from the UK which provides data on the effectiveness of the BNT162b2 Pfizer vaccine after the first dose, the surveillance report from Israel provides data on the effectiveness of BNT162b2 after the second dose. When taken together with the data from the report from the UK, the data from Israel should provide us a more comprehensive idea of the efficacy of BNT162b2 in the general population. Let us have a look at this report.

Background of the surveillance report from Israel
The report from Israel was done by the Israel Ministry of Health and by Pfizer. Israel launched the vaccination campaign on 20 December 2020, 12 days after the UK. Moreover, Israel used only BNT162b2 (Pfizer) for its nationwide vaccination programme.

The study analyzed nationwide surveillance data from 24 January to 3 April, 2021. The start of the study period corresponded to 14 days after the first individuals received their second BNT162b2 dose. By 3 April 2021, 72.1% of people aged 16 years and older were fully vaccinated with two doses of BNT162b2. Individuals with a history of severe allergic reactions to the vaccine components were not eligible to receive the vaccine.

The study aimed to estimate the effectiveness of two doses of BNT162b2 (second dose injected 21 days after the first dose, in accordance with the suggestion from Pfizer) against a range of SARS-CoV-2 outcomes (asymptomatic infection, symptomatic infection, and COVID-19-related hospitalisation, severe or critical hospitalisation, and death) in the general population in Israel. The study also evaluated the nationwide public-health impact following the widespread introduction of the vaccine.

The vaccine’s effectiveness against SARS-CoV-2 outcomes was calculated on the basis of incidence rates in fully vaccinated individuals (who had received the second dose of vaccine and had passed 7 days) compared with rates in unvaccinated individuals (who had not received any doses of the vaccine).

The data from the observational surveillance report from Israel vaccination campaign The report showed that BNT162b2 is highly effective across all age groups (16–24, 25–34, 35–44, 45–54, 55–64, 65–74, 75–84, and ≥85 years) in preventing a range of SARS-CoV-2 outcomes. Among adults aged 16 years and older, the vaccine effectiveness was 95.3% against SARS-CoV-2 infection at 7 days or longer after the second dose: 91.5% against asymptomatic SARS-CoV-2 infection, 97.0% against symptomatic COVID-19, 97.2% against COVID-19-related hospitalisation, 97.5% against severe or critical COVID-19-related hospitalisation, and 96.7% against COVID-19-related death.

According to the test samples of people with COVID-19 taken during the period of the study, 94.5% of the SARS-CoV-2 infections were from the B.1.1.7 variant. The test results indicated that BNT162b2 is highly effective against the SARS-CoV-2 variant B.1.1.7, which was first identified in the UK, and later reported in Israel on 23 December, 2020.

In all age groups, as vaccine coverage increased, the incidence of SARS-CoV-2 infection declined. The early reductions in incident cases of SARS-CoV-2 infections were observed in older age groups, which had higher and earlier vaccine coverage. The declines were observed for people aged 65 years and older starting in mid-January 2021, while the reductions were observed 3 to 4 weeks later among people aged between 16 and 24, when vaccine coverage for this age group began to increase. The incidence of COVID-19 hospitalisations, severe or critical hospitalisations, and deaths, were also declined accordingly.

The figures from the report showed that the declines of SARS-CoV-2 incidence continued even after the two phases of reopenings on 7 February and 21 February 2021, and the final lifting of the lockdown on 7 March 2021. These findings suggest that the vaccine coverage was the main contributor for the reductions in the incidence of SARS-CoV-2 infections, while the next is the nationwide lockdown measure.

Moreover, the SARS-CoV-2 incidence remained low even after the two phases of reopenings. This further suggests that vaccine coverage might provide a sustainable path towards resuming normal activity nationally.

Conclusion
The UK government has started giving BNT162b2 (Pfizer) to most adults aged under 40.² The report from Israel demonstrates that two doses of BNT162b2 are highly effective in preventing different SARS-CoV-2 infection outcomes, including severe disease and death, among different age groups. Moreover, there were steep and sustained declines in SARS-CoV-2 infection rate corresponding to increasing vaccine coverage. Therefore, unless you have a history of severe allergic reactions and are defined as not suitable to get the BNT162b2 Pfizer vaccination,³ it is worth receiving a full dosage of the vaccine in order to get protection from COVID-19.

References
1. E.J. Haas, F.J. Angulo, J.M. McLaughlin, et al. Impact and effectiveness of mRNA BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths following a nationwide vaccination campaign in Israel: an observational study using national surveillance data. Lancet, May 5, 2021 https://doi.org/10.1016/S0140-6736(21)00947-8 . Online ahead of print.
2. Under 40s to be offered alternative to AZ vaccine. By James Gallagher. BBC news, 7th May, 2021. https://www.bbc.co.uk/news/health-57021738
3. Pfizer-BioNTech COVID-19 vaccine overview and safety. Centers for Disease Control and Prevention. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/different-vaccines/Pfizer-BioNTech.html

Coronavirus (40) Nationwide COVID-19 immunization in the UK

Coronavirus (40) Nationwide COVID-19 immunization in the UK
Five months have passed since the UK started its vaccination rollout last December. You might wonder the concerns about the side-effects after vaccination and the efficacy of the vaccines against COVID-19 in the general population. Surveillance reports from the UK’s vaccination programme using Pfizer-BioNTech (BNT162b2, mRNA vaccine) and Oxford-AstraZeneca (ChAdOx1 nCoV-19, non-replicated adenovirus vectored vaccine) COVID-19 vaccines has been published recently.¹ Although the vaccination campaign in the UK is still ongoing, the data from the report gives us some idea of the above issues.

Background of the surveillance report from the UK
The surveillance report from the UK analysed data collected from individuals using a COVID Symptom Study app, which was developed by a health science company ZOE and was launched at the end of March 2020. The research is led by ZOE co-founder, Professor Tim Spector at King’s College London. Data collected is shared with and analysed by King's College London and ZOE research teams.

The reports covered the period from the first day of the vaccine campaign, 8 December 2020, to 10 March 2021. The nationwide vaccination programme in the UK prioritized senior citizens and the most vulnerable groups.² According to the COVID-19 vaccine monitoring statistics data provided by the NHS,³ by 14th March, at least one dose of vaccine had been given to the adults aged over 50, front-line health and social care workers (those who participated in the ZOE study had a median age of 46.1 years),⁴ staff working in care homes, clinically extremely vulnerable individuals, and the adults aged 16 to 65 years in an at-risk group.

The BNT162b2 (Pfizer) vaccination was first rolled out on 8 December 2020, while the ChAdOx1 nCoV-19 (Oxford/AstraZeneca) vaccination was first rolled out on 4 January 2021. Both vaccines are two-dose regimens. However, individuals will be given the second dose at 10-12 weeks after the first dose, rather than 21 days as per the guidance of the vaccine manufacturers. By the end of the analysis period, some people already had both doses of BNT162b2 (Pfizer) vaccines.

The COVID Symptom Study app allows self-reporting of systemic and local side effects for individuals who received one or both doses of the BNT162b2 (Pfizer) vaccine, or the first dose of the ChAdOx1 nCoV-19 (Oxford/AstraZeneca) vaccine. Side effects were monitored for the following 8 days after a vaccination. A subset of individuals also reported receiving a test for SARS-CoV-2 infection by either PCR or lateral flow test. The study also compared infection rates in a subset of vaccinated individuals (subsequently tested for SARS-CoV-2 with PCR or lateral flow tests) with infection rates in unvaccinated controls.¹

The side effects of both vaccines
During the analysis period, the COVID Symptom Study app received 627,383 reports of individuals being vaccinated: 282,103 received at least one dose of BNT162b2 (Pfizer), while 345,280 individuals reported being vaccinated with one dose of ChAdOx1 nCoV-19 (Oxford/AstraZeneca).

From the self-report system, it seems that systemic (whole body) side-effects were higher in participants who received ChAdOx1 nCoV-19 (Oxford/AstraZeneca). Systemic side-effects were reported by 13.5% and 22.0% of individuals after the first dose and the second dose respectively of BNT162b2 (Pfizer), while 33.7% of individuals receiveing the first dose of ChAdOx1 nCoV-19 (Oxford/AstraZeneca) reported systemic side-effects. The most commonly reported systemic side-effects were fatigue and headache for both vaccines. They were most frequently reported within the first 24 hours after vaccination, and lasted for about 1 day.

The reported local side-effects were more frequent than the systemic side-effects. However, by contrast with the systemic side-effects, local side-effects were more frequent in participants who received BNT162b2 (Pfizer): 71.9% and 68.5% of individuals reported local side-effects after the first dose and the second dose of BNT162b2, respectively, while 58.7% of individuals reported local side-effects after the first dose of ChAdOx1 nCoV-19. The most frequent local side-effects are tenderness and local pain around the injection site, which occurred most often on the day after injection and lasted for about 1 day. The less frequent side-effects include allergic skin reactions such as skin burning, rashes, and red welts on the lips and face, which was reported in 1.7% of 627,383 users across both types of vaccine.

Both systemic side effects and local side effects of both vaccines were more common among individuals with previous SARS-CoV-2 infection than among those without known past infection. After the first dose of BNT162b2 (Pfizer), systemic side effects and local side effects were 2.9 times and 1.2 times as high among individuals with previous SARS-CoV-2 infection than among those without known past infection. Meanwhile, after ChAdOx1 nCoV-19 (Oxford/AstraZeneca) vaccination, systemic side-effects and local side-effects were 1.6 times and 1.4 times as high among individuals with previous SARS-CoV-2 infection than among those without known past infection. Similar findings had been reported before.^5,6 It seems that the previous infection leads to a higher immune response, which is reflected by the systemic side-effects, in a subsequent infection.

In line with the above findings, among the individuals (28,207) who reported having two BNT162b2 (Pfizer) doses, a higher percentage of systemic side-effects were being reported in individuals after the second dose. There were 3325 (11.7%) reporting at least one systemic side effect after the first dose, compared with 6216 (22.0%) after the second dose.

Infection rates after the vaccination of both vaccines
The study analysed infection rates at 0–4, 5–11, 12–20, 21–44, and 45–59 days after vaccination. It was found that the infection risk was significantly reduced starting at 12 days after the first dose of BNT162b2 (Pfizer), reaching 69% at 21–44 days and 72% after 45–59 days. For ChAdOx1 nCoV-19 (Oxford/AstraZeneca), the risk of infection was significantly reduced starting at 12 days after the first dose, reaching 60% later on.

Moreover, the data showed that the vaccines were more effective in younger and slimmer people with no more than one illness. For both vaccines, the reduction of infection was more significant in individuals aged 55 years or younger than in individuals older than 55 years; it was also more significant in those without comorbidity than in those with one or more comorbidities, and in individuals with a BMI of less than 30 kg/m² than in those with BMI of 30 kg/m² or higher.

The surveillance report showed us that the systemic side-effects of both vaccines, BNT162b2 and ChAdOx1 nCoV-19, are not highly prevalent. And the findings that the efficacy of the two vaccines are more than 60% 12 days after the injection should give us confidence to have vaccination if we have not had one. This should also encourage the individuals to have the second dose in order to get a higher protection from the vaccine.

References
1. C. Menni, K. Klaser, A. May, et al. Vaccine side-effects and SARS-CoV-2 infection after vaccination in users of the COVID Symptom Study app in the UK: a prospective observational study. Lancet Infect Dis., 2021 Apr 27. S1473-3099(21)00224-3. doi: 10.1016/S1473-3099(21)00224-3.
2. COVID-19 vaccination first phase priority groups. NHS website. Updated 23 April 2021. https://www.gov.uk/government/publications/covid-19-vaccination-care-home-and-healthcare-settings-posters/covid-19-vaccination-first-phase-priority-groups
3. COVID-19 vaccination statistics. By NHS. https://www.england.nhs.uk/statistics/wp-content/uploads/sites/2/2021/03/COVID-19-weekly-announced-vaccinations-18-March-2021.pdf
4. V.J. Hall, S. Foulkes, A. Saei, et al. COVID-19 vaccine coverage in health-care workers in England and effectiveness of BNT162b2 mRNA vaccine against infection (SIREN): a prospective, multicentre, cohort study. Lancet. 2021; (published online April 23.)
5. F. Krammer, K. Srivastava, and V. Simon. Robust spike antibody responses and increased reactogenicity in seropositive individuals after a single dose of SARS-CoV-2 mRNA vaccine. medRxiv, 2021; published online Feb 1. doi: https://doi.org/10.1101/2021.01.29.21250653
6. J. Wise. COVID-19: people who have had infection might only need one dose of mRNA vaccine. BMJ, 2021 Feb 2;372:n308. doi: 10.1136/bmj.n308.

Coronavirus (39) India is the world's biggest supplier of vaccines

Coronavirus (39) India is the world’s biggest vaccine supplier
For the last couple of weeks, reports of the second wave of COVID-19 in India have caught the attention of the whole world. The daily figures rose to 379,459 new confirmed cases and 3,647 deaths due to COVID-19 yesterday in India¹ and are expected to continue to rise for another two weeks, with a peak of nearly five hundred thousand new cases a day and more than 5000 deaths per day due to COVID-19 by mid-May.²

The world is now more connected than before, so this wave of COVID-19 in India will definitely affect the world’s economy, as India is the sixth largest economy in the world.³ Moreover, mutations of the virus may evolve every time the virus is passed on, so the higher the number of cases of infection, the higher the chance of a new variant emerging with higher transmissibility and/or higher resistance to the currently-available vaccines and therapies against COVID-19.

However, as the crisis is hitting India, the news reports also showed us something we might not have known before: India is the world’s biggest supplier of vaccines.⁴ You might be interested to know more about the vaccine industry in India and how that industry is involved in manufacturing vaccines against COVID-19. Let us have a look at this issue in this blog post.

India is the world’s biggest supplier of vaccines
The seven largest vaccine manufacturers in India have an installed capacity to manufacture a total of 8.2 billion doses of different vaccines per year.⁵ The first two largest vaccine manufacturers in India can already produce about 2.5 million doses a day.⁶ These vaccine manufacturers play a very important role in providing vaccines against COVID-19 worldwide.

Serum Institute of India (SII): the largest vaccine manufacturer in India
The Serum Institute of India (SII) is based in Pune and was founded in 1966 by Dr. Cyrus Poonawalla. According to the company’s website, it is the world's largest vaccine manufacturer by number of doses produced and sold globally. The company mainly produces traditional vaccines: its products include Polio vaccine, Diphtheria, Tetanus, Pertussis, Hib, BCG, r-Hepatitis B, Measles, Mumps and Rubella vaccines. The vaccines produced are being used in about 170 countries in the world in their national immunization programmes. Around 65% of the children in the world receive at least one vaccine manufactured by SII.⁷

Last June, SII obtained permission from AstraZeneca to manufacture Covishield, the COVID-19 vaccine which was co-developed by the University of Oxford and AstraZeneca. Under the agreement, the company will supply a total of one billion doses of Covishield for low- and middle-income countries. The company was expected to produce 100 million doses of Covishield per month.⁸

However, there was a fire at one of its facilities in January. Moreover, due to the surge in number of domestic COVID-19 cases, the Indian government started halting the exports of Covishield in March. Only 64 million dose of Covishield were exported before the halt in exports, 28 million of which went to COVAX, an organization co-led by GAVI (a global vaccine alliance), the Coalition for Epidemic Preparedness Innovations and WHO, one of the aims of which is to guarantee fair and equitable delivery of COVID-19 vaccines to poorer countries.⁸ This delayed planned deliveries of Covishield to 64 lower-income countries through COVAX.

In addition to Covishield, SII is also set to launch the production of millions of a protein vaccine, Covovax, developed by Novavax.⁹ The company’s CEO, Adar Poonawalla, said on Twitter that the vaccine is expected to be produced by September 2021. The company has initiated the Phase II and Phase III bridging trials for this vaccine.⁹

Bharat Biotech: the second largest vaccine manufacturer in India
The second largest vaccine manufacturer in India is Bharat Biotech. It was found in 1996 and is currently based in Hyderabad. The company owns over 160 patents and its products are used in over 123 countries. Since its establishment, the company has delivered over 4 billion vaccine doses worldwide. Its key focus is to develop and provide vaccines and therapeutics to the developing world.¹⁰

Since the beginning of the pandemic last year, Bharat Biotech collaborated with the Indian Council of Medical Research to develop an inactivated vaccine, Covaxin, against COVID-19. The company was given permission in January 2021 by the Indian government for emergency use of Covaxin. It is expected the company can make 12.5 million doses each month.⁸

Bharat Biotech is also conducting clinical trials for a intranasal viral vectored vaccine against COVID-19. The chairman of the company, Krishna Ella, expected that the vaccine could be available to the market by June this year if a protocol for all phases of clinical trials is clearly defined by the Indian government. If the company obtains emergency use approval from the government, he expected that the company can produce more than 1 billion doses.⁵

Other vaccine manufacturers in India
Besides the two biggest vaccine manufacturers, the other large vaccine manufacturers in India also fully participate in the campaign to manufacture vaccines against COVID-19. Biological E., another vaccine manufacturer based in Hyderabad, has signed a contract with Johnson & Johnson to produce 600 million doses of Ad26.COV2.S, a one-shot, adenovirus-vectored vaccine which has been approved to be used in the US.⁵

Moreover, Biological E. also cooperates with US organizations to develop an additional vaccine against COVID-19, a recombinant protein-subunit vaccine including antigen developed by Texas Children’s Hospital Center for Vaccine Development and advanced adjuvant CpG 1018TM from Dynavax. Biological E. announced on 24th April that it has successfully completed the Phase I/II clinical trial of this COVID-19 vaccine candidate in India and received approval to start the Phase III clinical trial from the Central Drugs Standard Control Organization- Subject Expert Committee.¹¹

Biological E. was founded in 1953 as the first private-sector biological products company in India and the first pharmaceutical company in Southern India. It develops, manufactures and supplies vaccines and therapeutics. Its vaccine products are sold to over 100 countries.¹¹

In addition, Dr. Reddy’s Laboratories, together with Panacea Biotech, Stelis Biopharm, Gland Pharma and Virchow Biotech, are about to produce an adenovirus vaccine, Sputnik V from Russia, for domestic use since the approval of its restricted use by the Indian government on the 12th of this month. It is expected that 850 million doses of Sputnik V per year could be produced from these vaccine manufacturers.⁵

Other than manufacturing COVID-19 vaccines that were developed elsewhere, there are several vaccine companies in India that developed COVID-19 vaccines by themselves, although most of them are currently far away from being launched. Among the COVID-19 vaccines undergoing clinical trials, a DNA plasmid-based vaccine, ZyCov-D, developed by Ahmedabad-based company Zydus Cadila, is in Phase 3 trials, and the initial data from the study is expected to be ready by May 2021.^12,13 The production of the ZyCoV-D vaccine has started with a yearly capacity of 240 million doses. It is expected to get emergency use authorization in May or June.¹⁴

Hopefully with the production of different COVID-19 vaccines by the vaccine manufacturers in India, and the ease of the export ban of raw material for vaccines from the US, the production of COVID-19 vaccines in India could be ramped up to its full capacity to provide as much vaccine as possible in time to alleviate the dire situation in India.



References
1. https://www.worldometers.info/coronavirus/country/india/
2. IIT scientists revise prediction on when COVID cases could peak in India. Mint, 6 Apr 2021. https://www.livemint.com/news/india/iit-scientists-revise-prediction-on-when-covid-cases-could-peak-in-india-11619437014161.html
3. "World Economic Outlook Database, April 2021". IMF.org. International Monetary Fund. April 2021. Retrieved 6 April 2021.
4. Why India's Covid crisis matters to the whole world. By Rebecca Morelle. BBC news, 28th April, 2021. https://www.bbc.co.uk/news/world-asia-india-56907007
5. How much vaccine can India make? And the catch...By Rai Vinaykumar. Business Today, April 14, 2021. https://www.businesstoday.in/coronavirus/after-launching-how-much-vaccine-can-india-make-and-the-catch/story/436474.html
6. India’s vaccine crisis is a warning to the world. By Grace Browne. WIRED, 29 April, 2021. https://www.wired.co.uk/article/india-vaccine-production
7. Serum Institute of India website. https://www.seruminstitute.com/about_us.php
8. India’s COVID-vaccine woes — by the numbers. How an explosion of coronavirus cases in India is putting global vaccine supplies at risk. T.V. Padma, Nature news, 15 April, 2021. https://www.nature.com/articles/d41586-021-00996-y
9. Serum Institute to delay launch of Novavax vaccine in India. Pharmaceutical Technology, 29 Mar 2021. https://www.pharmaceutical-technology.com/news/serum-institute-novavax-vaccine/
10. Bharat Biotech website. https://www.bharatbiotech.com
11. Biological E. Limited gets CDSCO nod to start Phase III clinical trial of its COVID-19 vaccine candidate. Biological E. press release, April 24, 2021. https://www.biologicale.com/news.html
12. DBT-BIRAC supported indigenously developed DNA vaccine candidate by Zydus Cadila, approved for Phase III clinical trials. pib.gov.in. Press Information Bureau, 3 January 2021.
13. Cadila Healthcare testing two-shot regimen for ZyCoV-D, data likely by May. By Das, Sohini. Business Standard, 22 April 2021. https://www.business-standard.com/article/current-affairs/cadila-healthcare-testing-two-shot-regimen-for-zycov-d-data-likely-by-may-121042200011_1.html
14. Cadila Healthcare starts production of Covid vaccine candidate. Mint news, 27 April 2021. https://www.livemint.com/companies/news/cadila-healthcare-starts-production-of-covid-vaccine-candidate-11619244017749.html

Coronavirus (38) South Africa variant of SARS-CoV-2 (cont'd)

Coronavirus (38) South Africa variant of SARS-CoV-2
In the last blog post, we’ve seen that the B.1.351 variant from South Africa is resistant to the antibodies in convalescent blood from most of the patients who have recovered from COVID-19, and it is also highly resistant to one of the currently-approved monoclonal antibody therapies to COVID-19. This blog post presents you with data on the efficacy of the vaccines that have been granted emergency use for COVID-19 in the UK, against the variant B.1.351.

B.1.351 is highly resistant to mRNA vaccines: Moderna mRNA-1273 and Pfizer BNT162b2
In order to check the efficacy of the mRNA vaccines to different variants, including variant B.1.351 and the original strain of SARS-CoV-2, researchers from Columbia University took blood samples from the volunteers who had received a complete course of either one of the two mRNA vaccines in the initial phase of clinical trials, mRNA-1273 from Moderna (12 participants) and Pfizer BNT162b2 (10 participants), and then performed neutralization tests* against the variants. The blood samples were collected at least 7 days after the last dose of vaccination in order to obtain serum with as high level of immunity as possible.¹

They found that, when compared to the original strain, the overall neutralizing activity from the blood samples taken from the participants vaccinated with Moderna mRNA-1273 or with Pfizer BNT162b2, is significantly lower against the B.1.351 variant.¹ According to this study, the overall neutralizing activity against B.1.351 was 12.4-fold lower than the original strain using blood samples from people vaccinated with Moderna mRNA-1273, and 10.3 fold lower using blood samples from people vaccinated with Pfizer BNT162b2.¹

These results reflect the fact that while both the mRNA vaccines are highly protective against the original strain, they confer much weaker protection from infection by the B.1.351 variant. The people vaccinated with full course of either Moderna mRNA-1273 or Pfizer BNT162b2 still have a very high chance of being infected and getting sick even when high immunity from the vaccines is attained.

When the serum from vaccinated individuals was used to test against pseudoviruses with spike genes containing different mutations found in B.1.351, the researchers found that the E484K mutation confers the resistance to neutralization.¹

AZD1222 has low efficacy towards B.1.351
A joint clinical trial study with scientists from the UK and South Africa showed that the efficacy of the two-dose regimen of adenovirus vaccine AZD1222 from AstraZeneca against B.1.351 was only 10.4%,² whereas the efficacy of AZD1222 against the initial strain of SARS-CoV-2 can be as high as 90%.³

The study was conducted in South Africa between late June and early November last year, when the variant B.1.351 was emerging. It was a multi-centre, double-blind, randomized, controlled trial to assess the safety and efficacy of AZD1222 in people not infected with the human immunodeficiency virus (HIV). Adult participants below the age of 65 were assigned to receive two doses of vaccine or placebo 21 to 35 days apart.² In the primary end-point analysis, 23 of 717 placebo recipients (3.2%) vs 19 of 750 vaccine recipients (2.5%) developed mild-to-moderate COVID-19, resulting in an efficacy of 21.9% from AZD1222.²

The efficacy result of AZD1222 from the clinical study in South Africa was very different from the previous report.³ However, sequencing analysis of the samples from the 42 participants with COVID-19 provided an explanation. It was found that 39 of the cases were caused by the B.1.351 variant. This led to the finding that vaccine efficacy against B.1.351 was only 10.4%. The study also found that incidence of serious adverse events was nearly equal between the vaccine and placebo groups.²

From this study, it was found that the adenovirus vaccine AZD1222 cannot very much protect vaccinated people against mild-to-moderate COVID-19 due to the B.1.351 variant.²

Conclusion
The B.1.351 South African strain emerged last August and has spread globally since then. Reports showed that the variant will not cause more serious illnesses and is not more deadly than the initial SARS-CoV-2 strain that causes COVID-19. Those people, such as the elderly and the ones with underlying health conditions, who are at high risk under the initial strain are at a similar risk level under the B.1.351 strain.

Although the South Africa variant B.1.351 has 50% higher transmissibility than the initial strain, we may not need to be too worried about the threat from this variant yet. B.1.1.7, one of the dominant strains in the UK, is also 50% higher in transmissibility than the initial strain, yet the COVID-19 infection rate and death toll in the UK is much lower than before. This means that variant strains even with higher transmissibility than the original strain can be contained, although it is not yet known for certain to what extent this containment was due to lockdowns (which will also apply to B.1.351) versus vaccines (which will not).

However, the concern is that the current therapies and vaccines designed against the original virus strain that cause COVID-19 will not work as well against the B.1.351 variant, as shown from the research studies presented in these two blog posts. Moreover, experience from clinical studies of COVID-19 vaccines in South Africa undertaken by Novavax, Janssen and Oxford/AstraZeneca also suggest that the variant B.1.351 can still cause infection even on the people who had been infected with the original strain of SARS-CoV-2. This shows that the immunity conferred from the previous infection by the original strain seems not strong enough to provide protection for the subsequent infection from the variant B.1.351.^2,4,5

Therefore, until the B.1.351 variant is totally contained in the UK and/or an effective therapy or vaccine is available, we should stay cautious while the UK government is easing the lockdown restrictions.



*Neutralization is a process where the vaccine/monoclonal antibody acted against a pathogen, such as virus. A pathogen can be highly neutralized by vaccine/monoclonal antibody, which means its activity can be diminished or abolished by the vaccine/monoclonal antibody, i.e. the vaccine or monoclonal antibody is effective against the pathogen.
**Pseudovirus used in the experiments on SARS-CoV-2 refers to a retrovirus that is genetically engineered to carry the glycoprotein protein sequence of SARS-CoV-2 (the initial strain or the sequence with mutation(s) found in the SARS-CoV-2 variants) in order to test the efficacy of the drug or vaccine, or to find out the mutation(s) responsible for the change in efficacy of the drug or vaccine. Pseudoviruses are capable of replicating only once, while the SARS-CoV-2 virus and its variants are highly infectious. Therefore, pseudovirus is very much preferred to be used by laboratories which do not meet high biosafety level (BSL) requirements to do testing on the real virus.



References
1. P. Wang, M.S. Nair, L. Liu, et al. Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7. Nature. 2021. PMID: 33684923
2. S.A. Madhi, V. Ballie, C.L. Cutland, et al. Efficacy of the ChAdOx1 nCoV-19 Covid-19 vaccine against the B.1.351 variant. NEJM, March 16, 2021. DOI: 10.1056/NEJMoa2102214
3. M. Voysey, S.A.C. Clemens, S.A. Madhi, et al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet. 2021 Jan 9;397(10269):99-111.
4. Novavax COVID-19 vaccine demonstrates 89.3% efficacy in UK Phase 3 trial. Novavax press release, Jan 28, 2021. https://ir.novavax.com/news-releases/news-release-details/novavax-covid-19-vaccine-demonstrates-893-efficacy-uk-phase-3
5. Johnson & Johnson COVID-19 vaccine authorized by U.S. FDA for emergency use -- first single-shot vaccine in fight against global pandemic. J&J press release, February 27, 2021. https://www.jnj.com/johnson-johnson-covid-19-vaccine-authorized-by-u-s-fda-for-emergency-usefirst-single-shot-vaccine-in-fight-against-global-pandemic

Coronavirus (37) South Africa variant of SARS-CoV-2

Coronavirus (37) South Africa variant of SARS-CoV-2 (a)
The rollout of vaccination against COVID-19 in the UK started from early December last year. Over 32 million people in the UK have received at least one dose of a coronavirus vaccine until now, according to the data from the government website.¹ With all the people over-50s and high-risk groups having been offered the first dose,² the daily number of people tested positive decreased to 3568 from the peak of 81,000.¹ The decrease in death toll due to the disease is more significant. Only 13 people who had had a positive test result for COVID-19 died within 28 days of the first positive test.¹ So far the figures demonstrated that the UK has successfully lowered the infection rate and suppressed the effect of the disease.1 Whether these improvements are attributed to the national lockdowns or to the vaccination programme, or both, we don’t know.

However, the report of an emerging variant of SARS-CoV-2, the virus that causes COVID-19, from South Africa reminds us to be cautiously optimistic.³ According to the Director of the Rosaline Franklin Institute, the progress of national reopening may be delayed if the South Africa variant has really taken off.⁴

What is the South Africa variant of SARS-CoV-2? Why should we pay attention to its emergence in the UK? The US Centers for Disease Control and Prevention (CDC) website lists in a table the research studies on the South Africa variant. Let us have a look at the results of these research studies in this and the next blog post.⁵ You may get some ideas for the reasons of being concerned about the variant.

The South Africa variant of SARS-CoV-2
The South Africa variant of SARS-CoV-2 is also referred to as B.1.351. South Africa authorities named the variant as 20H/501Y.V2 or 501Y.V2, because of a N501Y mutation. Its first emergence can be traced back to July or August 2020 in the Eastern Cape province of South Africa, after the first epidemic wave in the worst-affected Nelson Mandela Bay within the Eastern Cape Province.⁶ The virus strain later spread across the country and even to other parts of the world, including the UK, via international travel.

The variant is also named VOC-20DEC-02 (Variant of Concern, year 2020, month December, variant 02) by UK authorities. The name is linked with the time when the variant was first sequenced in the UK in December 2020.⁷ Data up to 7 April showed a total of 533 confirmed cases, detected by PCR, since then.⁷ The rise in the number of cases is dramatic: there were 44 confirmed cases detected in Wandsworth and Lambeth in South London in a single day last week.^3,4 This rises an alarm.

Genomic characteristics of B.1.351
B.1.351 is characterised by nine mutations in the spike gene of SARS-CoV-2, including three (K417N, E484K and N501Y) at important residues in the receptor-binding domain (RBD). B.1.351 also carries mutation D614G. The mutation emerged in late January or early February 2020. Within a few months, D614G mutation replaced the original SARS-CoV-2 strain in China and became the dominant form of the virus circulating globally by June 2020.⁸

The variant B.1.351 raises concerns because of its increased transmissibility. Moreover, the variant has extensive mutations in the spike gene, which is the major target of neutralizing* antibodies. The mutations in this area may impair the efficacy of the current monoclonal antibody therapies and vaccines which are directed against the spike region of the SARS-CoV-2 virus.

Transmissibility of B.1.351
The Centre for the Mathematical Modelling of Infectious Diseases (CMMID) at the London School of Hygiene & Tropical Medicine (LSHTM) and Stellenbosch University in South Africa estimated that B.1.351 variant is about 50% higher in transmissibility than previously circulating strain. The increase in transmissibility is similar to the variant dominating in the UK nowadays, which is referred to as B.1.1.7.⁹ Both B.1.351 and B.1.1.7. have mutation D614G. Research studies found that variants with this mutation spread more quickly than viruses without this mutation.¹⁰

Mild neutralization by convalescent plasma***
Scientists from Columbia University took plasma from 20 patients recovered from COVID-19 more than one month after documented SARS-CoV-2 infection. They found that most plasma samples (16 out of 20) lost more than 2.5-fold neutralizing activity against B.1.351, compared to the wild type. The loss of plasma neutralizing activity against B.1.351 was found to be largely attributed to the E484K substitution.¹¹

The low neutralizing ability against B.1.351 by the convalescent blood from COVID-19 patients indicates the high possibility of re-infection. The situation was observed in the Novavax vaccine trial in South Africa. The study found that recipients who received the placebo with previous SARS-CoV-2 infection were not protected against a subsequent exposure to B.1.351;¹² in Manaus, Brazil, 76% of the population was infected in the first wave of SARS-CoV-2 infection, but the city still suffered with the sweeping second wave of infection due to P.1 variant, which shared most of the substitution mutations including E484K with B.1.351.¹¹ These two examples are sufficient enough to remind us to stay cautious even if we have been infected once before by the initial strain of SARS-CoV-2.

Very low efficacy of monoclonal antibody therapies to B.1.351
The Food and Drug Administration (FDA) of the US has granted the emergency use of 2 combination therapies for COVID-19: bamlanivimab with etesevimab, and REGEN-COVTM (casirivimab with imdevimab). Ingredients of both regimens are monoclonal antibodies (the drug names end with “mab”, which means monoclonal antibody) which bind to non-overlapping epitopes of the spike protein receptor binding domain (RBD) of SARS-CoV-2 and stop the virus from infecting cells. They are allowed for treatment of mild to moderate COVID-19 in adults and paediatric patients (12 years of age and older, weighing at least 40kg), with positive results of direct SARS-CoV-2 viral testing, and at risk of progressing to severe COVID-19 and/or hospitalization.^13,14

According to the document from the FDA, the REGEN-COVTM therapy against pseudovirus** expressing all spike protein substitutions found in the B.1.351 lineage, had similar efficacy to the pseudovirus expressing wild type.¹³ However, the activity of bamlanivimab with etesevimab against pseudovirus expressing B.1.351 mutation substitution was greatly reduced to >45 fold, compare to the pseudovirus expressing wild type.¹⁴ This means the therapy with bamlanivimab and etesevimab together has very limited ability to diminish the activity of the variant B.1.351.

In fact, when the activity of the four drugs bamlanivimab, etesevimab, casirivimab, and imdevimab were individually examined against the authentic wild type SARS-CoV-2 virus and its authentic B.1.351 variant, only imdevimab, one of the ingredients of REGEN-COVTM therapy, retained the same activity. The efficacy of each of the other three drugs against B.1.351 variant was completely or markedly abolished, compared with the wild type.¹¹

These findings suggest that antibody treatment of COVID-19 might need to be modified in areas where B.1.351 and related variants are prevalent.



*Neutralization is a process which the vaccine/monoclonal antibody acted against a pathogen, such as virus. A pathogen can be highly neutralized by vaccine/monoclonal antibody, which means its activity can be diminished or abolished by the vaccine/monoclonal antibody, i.e. the vaccine or monoclonal antibody is effective against the pathogen.
**Pseudovirus used in the experiments on SARS-CoV-2 refers to a retrovirus that is genetically engineered to integrate the glycoprotein protein sequence of SARS-CoV-2 (the initial strain or the sequence with mutation(s) found in the SARS-CoV-2 variants) in order to test the efficacy of the drug or vaccine, or to find out the mutation(s) responsible for the change in efficacy of the drug or vaccine. Pseudoviruses are capable of replicating only once, while the SARS-CoV-2 virus and its variants are highly infectious. Therefore, pseudovirus is very much preferred to be used by laboratories which do not meet high biosafety level (BSL) requirements to do testing on the real virus.
***Convalescent serum is taken from the blood from people who have recovered from an illness. The prior infection to the pathogen, which caused the illness, lead to the production of antibodies specific to the pathogen. The convalescent serum therefore could be used as a source of antibodies to help people who are suffering from the same infection.



References
1. https://coronavirus.data.gov.uk/details/vaccinations
2. Covid vaccine: All over-50s and high risk groups offered first dose. BBC new, 13 April, 2021.
3. Covid-19: Vaccination milestone and variant cluster in south London. BBC news, 13 April, 2021.
4. South Africa coronavirus variant: What is the risk? BBC news, 13 April, 2021.
5. SARS-CoV-2 variant classifications and definitions. CDC of the US’s website, updated Mar. 24, 2021. https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/variant-surveillance/variant-info.html
6. H. Tegally, E. Wilkinson, M.Giovanetti, et al. Emergence and rapid spread of a new severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) lineage with multiple spike mutations in South Africa. Medrxiv, December 22, 2020. https://doi.org/10.1101/2020.12.21.20248640
7. Variants of concern or under investigation: data up to 7 April 2021. https://www.gov.uk/government/publications/covid-19-variants-genomically-confirmed-case-numbers/variants-distribution-of-cases-data#Variant2
8. SARS-CoV-2 variants. WHO’s disease outbreak news, 31 December 2020. https://www.who.int/csr/don/31-december-2020-sars-cov2-variants/en/
9. C.A.B. Pearson, T.W. Russell, N.G. Davies, et al. Estimates of severity and transmissibility of novel South Africa SARS-CoV-2 variant 501Y.V2. Paper under peer review. First online: 11-01-2021. Last update: 11-01-2021. https://cmmid.github.io/topics/covid19/sa-novel-variant.html
10. B. Korber, W.M. Fischer, S. Gnanakaran, et al. Tracking changes in SARS-CoV-2 spike: Evidence that D614G increases infectivity of the COVID-19 virus. Cell, 2020 Aug 20;182(4):812-827.e19. doi: 10.1016/j.cell.2020.06.043. Epub 2020 Jul 3.
11. P. Wang, M.S. Nair, L. Liu, et al. Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7. Nature, 8 March, 2021. doi: 10.1038/s41586-021-03398-2.
12. Novavax COVID-19 vaccine demonstrates 89.3% efficacy in UK Phase 3 trial. Novavax press release, Jan 28, 2021. https://ir.novavax.com/news-releases/news-release-details/novavax-covid-19-vaccine-demonstrates-893-efficacy-uk-phase-3
13. Fact sheet for health care providers’ emergency use authorisation (EUA) of REGEN-COVTM (casirivimab with imdevimab)
14. Fact sheet for health care providers' emergency use authorisation (EUA) of bamlanivimab and etesevimab

About Novavax

About Novavax
Novavax is a biotechnology company based in Maryland, USA. It was found in 1987 and has become known worldwide since its participation in the race to produce a vaccine against COVID-19. However, unlike other young biotech start-ups in the same race, such as Biontech and Moderna, the road Novavax took has been relatively tough. Let’s have a look at the technology, the products and the history of the company in this blog.

The technology used by Novavax
Novavax has a proprietary recombinant technology platform (Sf9/BV) for the production of antigens of vaccine that can induce immune responses.¹ The two major components of the recombinant technology are baculovirus, a virus commonly attacked insects, and Sf9 moth cells.

Once the whole genome sequence of a pathogen has been identified, Novavax then identifies the genetic sequences that may trigger the immune responses in the host cells. Baculovirus used by the company is genetically engineered to carry the selected genetic sequence used to encode a vaccine antigen that can trigger an immune response. The recombinant baculovirus is then put into Sf9 moth cells by infection. Making use of the Sf9’s cellular post-transcriptional and post-translational machinery, the protein antigens expressed from the recombinant baculovirus are able to fold and modify themselves properly into their native forms. (Antigen in native configuration is necessary for optimized biologic immune responses for active immunity.) The Sf9 insect cell is like a manufacturing company which scales up production of antigens with native confirmation. The antigen produced is then harvested and purified as multimeric particles.¹

Besides the antigen, Novavax also put its proprietary adjuvent, called Matrix-M, into its vaccine. Matrix-M is composed of 40-nanometer particles, based on saponin extracted from the Quillaja saponaria Molina bark, together with cholesterol and phospholipid.¹ Matrix-M induces the influx of antigen presenting cells (APC), which enhance activated CD4+ and CD8+ T cells, long-lasting memory B cells, and APC populations. In general, Matrix-M generates potent, robust, and long-lasting protective immune responses. Therefore, the addition of Matrix-M in a vaccine can lower the dose of antigen required to achieve the desired immune response, and thus increases supply and manufacturing capacity using the same amount of antigens. Overall, the vaccine produced in this way is cheaper.

As the antigen in the vaccine is in protein form, which is more stable than the vaccine made of mRNA, Novavax’s vaccine is easier to transport and can be stored at room temperature for at least 24 hours.

Novavax has previous experience working with other coronaviruses, such as Middle East Respiratory Syndrome (MERS-CoV) and Severe Acute Respiratory Syndrome (SARS). The two vaccine candidates demonstrated strong immunity and 100% protection in preclinical tests, but have never been put on the market for some reasons. This experience enabled the company to mobilize quickly against COVID-19.²

The hardship Novavax has gone through
Novavax has been established for more than 33 years. However, the biotech company has no single vaccine product being approved during these years. In January 2020, before the pandemic attacked the world, the company experienced a short interest which hit 30 percent of its share price. A year before that, Novavax was on the edge of closing, facing de-listing from Nasdaq. It had to lay off 120 manufacturing and quality-control staff, one-third of its staff.³

When we look back, Novavax has faced difficulties right at the beginning of its history. The company was founded in 1987 to develop “novazone” particles for vaccine delivery. But it soon changed its direction of the usage of the particles into hormone delivery. Its research and development in the women’s health business unfortunately had to be halted by 2005 due to unfavourable position in the competition market and concerns over the risk of breast cancer after oestrogen treatment.³

Since then, Novavax has been working on vaccines for SARS, MERS, Ebola, influenza, and Respiratory Syncytial Virus (RSV), a common virus that can be deadly for babies and older adults.² This development of the vaccine to the RSV virus caused crisis after crisis in the company and almost drove the company to closure. In 2016, a Phase 3 clinical trial in older people failed due to not enough cases being available to reach a firm conclusion, and a diagnostic tool not widely available at the time. The company did not have enough funds to reinvent the Phase 3 trial and the company’s stock dropped 83 percent in one week. Later when the company was able to start a clinical trial of the RSV vaccine on pregnant women with the help of funding from the Gates Foundation, the trial failed and led to another financial crisis for the company in 2019 as mentioned above. In order to avoid being de-listed by Nasdaq, the company initiated a reverse stock split to lift its share price. It also had to sell its manufacturing facility in order to survive through the crisis.^3,4

The promising products Novavax is developing
After surviving from the crisis, Novavax now has two promising vaccine candidates, other than the vaccine against COVID-19. One of them is NanoFlu™, a quadrivalent influenza nanoparticle vaccine. It is currently in a Phase 3 clinical trial to address key factors that can lead to the poor effectiveness of currently approved flu vaccines. Another one is ResVax™, the RSV vaccine that the company has long been developing. This is now in a Phase 3 clinical programme.²

Partnerships and manufacturing
Novavax sold its manufacturing facility in 2019 just before the company got funding from the US government to develop the COVID-19 vaccine. In order to fulfil the manufacturing capacity for clinical trials, the future vaccine supply, and rapid distribution across the world if and when its COVID-19 vaccine is approved for use, the company stretched itself in co-operating with many other pharmaceutical companies to produce the vaccine.

Initially, the company used a Maryland-based drug manufacturer, Emergent BioSolutions, to make initial doses for the clinical trials. Later, it partnered with different drug makers worldwide for production of vaccine if the vaccine candidate is approved: Serum Instititue of India Private Limited (SIIPL) for global production of the antigen component of its COVID-19 candidate;^5,6 the National Research Council’s Biologics Manufacturing Centre for vaccine supply in Canada;⁷ FUJIFILM Diosynth Biotechnologies (FDB) manufacturing site in UK to manufacture the antigen component of its COVID-19 vaccine in the UK;⁸ Takeda for local manufacturing and commercialization in Japan;⁹ and SK Biosciences for the manufacturing of Novavax’s protein antigen for the supply in South Korea.¹⁰ In addition, Novavax recently acquired a factory, Praha Vaccines, in the Czech Republic, to provide extra annual capacity of over 1 billion doses of antigen for its COVID-19 vaccine candidate, starting in 2021.¹¹

In the US, Novavax is co-operating with FUJIFILM Diosynth Biotechnologies (FDB) to manufacture bulk drug substances for its COVID-19 vaccine candidate. The manufactoring site of FDB in Morrisville has produced the first batch of the company’s COVID-19 candidate.¹² The company itself is also expanding its campus to accommodate rapid growth. It has secured two additional properties in order to support its immediate need for additional laboratory and office space for manufacturing, R&D and business operations.¹³

Given the potential of its technology to manufacture millions of doses of vaccine quickly, Novavax received 1.6 billion US dollars from the US government early last year to expand its manufacturing capacity. Moreover, the company obtained additional funds from other sources since then.⁴ Hopefully the vaccine can get approval very soon in order to add supply to relieve the worldwide demand for COVID-19 vaccines.





References
1. Recombinant nanoparticle vaccine technology. Novavax website. https://www.novavax.com/our-unique-technology#recombinant-nanoparticle-vaccine-technology
2. Novavax advances development of novel COVID-19 vaccine. Novavax press release, Feb 26, 2020. https://ir.novavax.com/news-releases/news-release-details/novavax-advances-development-novel-covid-19-vaccine
3. Novavax closes in on Covid triumph after 33 years of failure. By Hannah Kuchler. Financial Times, March 1, 2021. https://www.ft.com/content/22d3805e-c304-4d95-ae32-f559ff34886a
4. How a struggling company won $1.6 billion to make a coronavirus vaccine. By Katie Thomas and Megan Twohey. New York Times, July 16, 2020. Updated Dec. 30, 2020. nytimes.com/2020/07/16/health/coronavirus-vaccine-novavax.html
5. “Hope to launch Covovax by September 2021”: Serum Institute’s Adar Poonawalla on second COVID vaccine. By Hannah Kuchler. New York. 1 March, 2021. https://www.livemint.com/news/india/hope-to-launch-covovax-by-september-2021-serum-institute-s-adar-poonawalla-on-2nd-covid-vaccine-11616830157066.html
6. Novavax announces COVID-19 vaccine manufacturing agreement with Serum Institute of India, increasing Novavax’ global production capacity to over 2 billion doses annually. Novavax press release, Sep 15, 2020. https://ir.novavax.com/news-releases/news-release-details/novavax-announces-covid-19-vaccine-manufacturing-agreement-serum
7. Novavax announces memorandum of understanding to produce COVID-19 vaccine made in Canada. Novavax press release, Feb 02, 2021. https://ir.novavax.com/news-releases/news-release-details/novavax-announces-memorandum-understanding-produce-covid-19
8. Novavax and UK government announce collaboration and purchase agreement for Novavax’ COVID-19 vaccine candidate. Novavax press release, Aug 14, 2020. https://ir.novavax.com/news-releases/news-release-details/novavax-and-uk-government-announce-collaboration-and-purchase
9. Novavax and Takeda finalize license agreement for Novavax’ COVID-19 vaccine candidate in Japan; Takeda initiates Phase 1/2 trial in Japan. Novavax press release, Feb 26, 2021. https://ir.novavax.com/news-releases/news-release-details/novavax-and-takeda-finalize-license-agreement-novavax-covid-19
10. Novavax announces expanded collaboration and license agreement with SK Bioscience for 40 million doses of COVID-19 vaccine for South Korea. Novavax press release, Feb 15, 2021. https://ir.novavax.com/news-releases/news-release-details/novavax-announces-expanded-collaboration-and-license-agreement
11. Novavax expands large-scale global manufacturing capacity. Novavax press release, May 27, 2020. https://ir.novavax.com/news-releases/news-release-details/novavax-expands-large-scale-global-manufacturing-capacity
12. Novavax and FUJIFILM Diosynth Biotechnologies initiate large scale manufacturing of COVID-19 vaccine candidate. Novavax press release, Jul 23, 2020. https://ir.novavax.com/news-releases/news-release-details/novavax-and-fujifilm-diosynth-biotechnologies-initiate-large
13. Novavax announces facility expansion to support global vaccine development. Novavax press release, Nov 02, 2020. https://ir.novavax.com/news-releases/news-release-details/novavax-announces-facility-expansion-support-global-vaccine

Coronavirus (36) Protein subunit COVID-19 vaccine: NVX-CoV2373 developed by Novavax

Coronavirus (36) Protein subunit COVID-19 vaccine: NVX-CoV2373 developed by Novavax
A month ago, on 28th February, another COVID-19 vaccine candidate, NVX-CoV2373 (also called Covovax), developed by Novavax, had its interim report, with a 89.3% overall efficacy (95.6% efficacy against the original strain, 85.6% efficacy against the UK variant) established from Phase 3 trials in the UK.^1,2 This vaccine also provides significant protection against the variants dominating in South Africa.¹ Novavax has since started to seek authorization of NVX-CoV2373 from regulatory agencies, including the US Food and Drug Administration (FDA), the UK Medicines and Healthcare products Regulatory Agency (MHRA), the European Medical Agency (EMA), and Health Canada.³ Let us have a look at the vaccine in this blog post.

If approved, NVX-CoV2373 will be the first protein-based vaccine against COVID-19. The vaccine contains trimeric full-length SARS-CoV-2 spike glycoproteins,^# found on the surface of SARS-CoV-2, made using the company’s nanoparticle technology.⁴ It also contains saponin-based Matrix-M1™ adjuvant,^## a substance that helps to enhance the immune response to the vaccine.⁵

Like other vaccines, NVX-CoV2373 prepares the body to defend itself against the next attack from the SARS-CoV-2 infection. Since it only contains a fragment of the disease-causing virus SARS-CoV-2, it can neither cause COVID-19 nor replicate by itself. In other words, the vaccine is safer as no live components are involved.

According to the protocol of the clinical trials of the vaccine, the vaccination is a two-dose regimen (each with 5 µg trimeric SARS-CoV-2 recombinant S glycoprotein antigen adjuvanted with 50 µg Matrix-M1) injected muscularly, administered 21 days apart.⁶ The vaccine is stable at 2°C to 8°C and can be stored at room temperature for at least 24 hours. It can be shipped in a ready-to-use liquid formulation. Existing vaccine supply chain channels can be used for its distribution. Thus the cost spent in transportation, distribution, and storage of the vaccine is much lower than those for the mRNA vaccines.

History of development
On 26 February 2020, Novavax announced that it has produced several nanoparticle vaccine candidates for COVID-19.⁷ In early April, they were able to identify NVX-CoV2373, a SARS-CoV-2 full-length 1273 amino acid spike protein variant with mutations on 2 sites, as the most ideal vaccine candidate. NVX-CoV2373 demonstrates high immunogenicity and triggers high levels of neutralizing antibodies against SARS-CoV-2 in mice and baboons.^8,9

Phase 1
The Phase 1 randomized, observer-blinded, placebo-controlled trial included 131 healthy participants aged 18 to 59 years, and was rolled out in Australia at the end of May. The report from the study was posted online at a preprint server in August 2020, and the full peer-reviewed report came out in September.¹⁰

The study showed that NVX-CoV2373 was well-tolerated and the reactions in the participants after injection were generally mild. Following the first dose, tenderness and pain were the most frequent local symptoms. Systemic events were individually less frequent, with headache, fatigue and myalgia being reported most commonly. Similar to the other approved vaccines, the second dose caused greater reactions in the participants, although the majority of symptoms were still reported as ≤ Grade 1, which means quite a mild reaction. The symptoms generally disappeared in 2 days.¹⁰

Moreover, NVX-CoV2373 elicited neutralizing antibody concentrations greater than those in a pool of COVID-19 patients with clinically significant disease, indicating the high efficacy of the vaccine. The Matrix-M1 adjuvant induced antigen-specific polyfunctional CD4+ T-cell responses that were reflected in IFN-γ, IL-2, and TNF-α production on spike protein stimulation.¹⁰

Phase 1/2
The Phase 2 portion of the Phase 1/2 clinical trial to evaluate the safety, immunogenicity, and efficacy of NVX-CoV2373 began in August in both the United States and Australia.¹¹ The trial expanded on the age range of the Phase 1 portion by including older adults of 60-84 years of age, as approximately 50 percent of the trial population.

In addition, a Phase 2b clinical trial, which enrolled over 4400 participants, to assess efficacy of the vaccine, began in South Africa in August.¹² The study covered September through mid-January, the period when the SARS-CoV-2 variant was widely circulated in South Africa. In fact, the variant accounted for 92.6% of the symptomatic COVID-19 events detected in the study.^### Moreover, approximately 1/3 of the enrolled participants demonstrated prior COVID-19 infection by the original COVID-19 strain. Yet, the interim study report announced by Novavax last month still showed a 60% efficacy for the prevention of mild, moderate and severe COVID-19 disease in the 94% of the study population that was HIV-negative. These data provided two important findings:1. The prior infection with COVID-19 may not completely protect against subsequent infection by the variant widely circulated in South Africa; 2. Vaccination with NVX-CoV2373 provided significant protection against the variant dominating in South Africa.¹

Phase 3
A Phase 3 efficacy trial was started in the UK in late September, 2020.¹³ This trial enrolled more than 15,000 participants aged between 18 and 84 years inclusive, including 27% over 65.¹ As mentioned in the first paragraph of this blog post, the first interim analysis results came out last month and showed an overall vaccine efficacy of 89.3%, based on 62 cases of COVID-19 being found among the participants (56 cases were observed in the placebo group while 6 cases were observed in the NVX-CoV2373 group). Of these 62 cases, 61 were mild or moderate; only 1 was severe and was in placebo group.¹

At the time the study was initiated in the UK, a variant strain of SARS-CoV-2 was increasingly prevalent, with over 50% of the PCR-confirmed symptomatic cases: 32 variant, 24 non-variant, 6 unknown. When splitting the efficacy based on the strains of the SARS-CoV-2 being detected, from 56 of the 62 cases, the vaccine efficacy was found to be 95.6% against the original COVID-19 strain and 85.6% against the variant strain.¹

Phase 3 efficacy trial of COVID-19, PREVENT-19 (the PRE-fusion protein subunit Vaccine Efficacy Novavax Trial for COVID-19), was also initiated later in December, in the United States and Mexico.¹⁴ A few days ago, Novavax announced the complete enrolment of 30,000 participants, which included Latin (20%), African American (13%), native American (6%), Asian American (5%), and older adults (65 years and older, 13%).¹⁵ The result from the study should provide a better view on the safety and efficacy of the drugs on different ethnicities.

Supply agreements with countries
NVX-CoV2373 is quite a popular protein subunit vaccine. Until now, Novavax has established agreements for the supply of NVX-CoV2373 directly to the US, the UK, Canada, Australia, and Switzerland, and, through partnerships, supply to Japan, South Korea and India.^16,17 A purchase agreement with the UK government allowed the UK to buy 60 million doses of NVX-CoV2373. Fujifilm Diosynth Biotechnologies, in its Billingham, Stockton-on-Tees site in the UK, is responsible for manufacturing the antigen component of the vaccine to be provided to the UK.¹⁸





#Novavax researchers started with a modified spike gene of SARS-CoV-2. They inserted the gene into a different virus, called a baculovirus, and allowed it to infect moth cells. The infected cells produced spike proteins that spontaneously joined together to form spikes, as they do on the surface of the coronavirus. A similar method of growing and harvesting virus proteins is already used to make licensed vaccines for diseases including influenza and HPV.
##According to the Novavax website, “Novavax’ patented saponin-based Matrix-M adjuvant has demonstrated a potent and well-tolerated effect by stimulating the entry of antigen-presenting cells into the injection site and enhancing antigen presentation in local lymph nodes, boosting immune responses.
###A 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.



References
1. Covid-19: Novavax vaccine shows 89% efficacy in UK trials. BBC news, 29 January, 2021. https://www.bbc.co.uk/news/uk-55850352
2. Novavax COVID-19 vaccine demonstrates 89.3% efficacy in UK Phase 3 trial. Novavax press release, Jan 28, 2021. https://ir.novavax.com/news-releases/news-release-details/novavax-covid-19-vaccine-demonstrates-893-efficacy-uk-phase-3
3. Novavax announces start of rolling review by multiple regulatory authorities for COVID-19 vaccine authorization. Novavax press release, Feb 04, 2021. https://ir.novavax.com/news-releases/news-release-details/novavax-announces-start-rolling-review-multiple-regulatory
4. Recombinant nanoparticle vaccine technology. Novavax website. novavax.com/our-unique-technology.
5. S.E. Magnusson, A.F. Altenburg, K.L. Bengtsson, et. al. Matrix-M™ adjuvant enhances immunogenicity of both protein- and modified vaccinia virus Ankara-based influenza vaccines in mice. Immunol Res., 2018 Apr; 66(2):224-233.
6. Current protocol for Phase 3 clinical trial of NVX-CoV2373 in the US and Mexico. novavax.com/resources
7. Novavax advances development of novel COVID-19 vaccine. Novavax press release, Feb 26, 2020. https://ir.novavax.com/news-releases/news-release-details/novavax-advances-development-novel-covid-19-vaccine
8. Novavax identifies coronavirus vaccine candidate; Accelerates initiation of first in-human trial to mid-May. Novavax press release, Apr 08, 2020. https://ir.novavax.com/news-releases/news-release-details/novavax-identifies-coronavirus-vaccine-candidate-accelerates
9. J.H. Tian, N. Patel, R. Haupt, et. al. SARS-CoV-2 spike glycoprotein vaccine candidate NVX-CoV2373 immunogenicity in baboons and protection in mice. Nature Communications, 12, Article number: 372 (2021).
10. C. Keech, G. Albert, I. Cho, et al. Phase 1–2 trial of a SARS-CoV-2 recombinant spike protein nanoparticle vaccine. N Engl J Med 2020; 383:2320-2332. DOI: 10.1056/NEJMoa2026920
11. Novavax initiates Phase 2 portion of Phase 1/2 clinical trial of COVID-19 vaccine. Novavax press release, Aug 24, 2020. https://ir.novavax.com/news-releases/news-release-details/novavax-initiates-phase-2-portion-phase-12-clinical-trial-covid
12. Novavax initiates efficacy trial of COVID-19 vaccine in South Africa. Novavax press release, Aug 17, 2020. https://ir.novavax.com/news-releases/news-release-details/novavax-initiates-efficacy-trial-covid-19-vaccine-south-africa
13. Novavax initiates Phase 3 efficacy trial of COVID-19 vaccine in the United Kingdom. Novavax press release, Sep 24, 2020. https://ir.novavax.com/news-releases/news-release-details/novavax-initiates-phase-3-efficacy-trial-covid-19-vaccine-united
14. Novavax announces initiation of PREVENT-19 pivotal Phase 3 efficacy trial of COVID-19 vaccine in the United States and Mexico. Novavax press release, Dec 28, 2020. https://ir.novavax.com/news-releases/news-release-details/novavax-announces-initiation-prevent-19-pivotal-phase-3-efficacy
15. Novavax completes enrolment of PREVENT-19, COVID-19 vaccine pivotal Phase 3 trial in the United States and Mexico. Feb. 22, 2021. https://ir.novavax.com/news-releases/news-release-details/novavax-completes-enrollment-prevent-19-covid-19-vaccine-pivotal
16. Novavax and Commonwealth of Australia announce agreement in principle for acquisition of Novavax COVID-19 vaccine. Novavax press release, Nov 04, 2020. https://ir.novavax.com/news-releases/news-release-details/novavax-and-commonwealth-australia-announce-agreement-principle
17. Novavax and Government of Switzerland announce agreement in principle to supply COVID-19 vaccine. Novavax press release, Feb 03, 2021. https://ir.novavax.com/news-releases/news-release-details/novavax-and-government-switzerland-announce-agreement-principle
18. Novavax and UK government announce collaboration and purchase agreement for Novavax’ COVID-19 vaccine candidate. Novavax press release, Aug 14, 2020. https://ir.novavax.com/news-releases/news-release-details/novavax-and-uk-government-announce-collaboration-and-purchase