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