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

Coronavirus (35) Protein subunit vaccine against COVID-19: an introduction

Coronavirus (35) Protein subunit vaccine to COVID-19: an introduction
Since the rollout of the vaccination against COVID-19 in last December, over 15 million people in the UK have received at least one dose. According to the NHS website, reports of serious side effects, such as allergic reactions, have been very rare. No long-term complications or death caused by vaccination have been reported.¹

So far, I have introduced in my blog three different types of COVID-19 vaccine in different stages of development: inactivated vaccine, non-replicating viral vector vaccine, and mRNA vaccine. Today in this blog post, I am going to introduce to you another type of vaccine for COVID-19: the protein subunit vaccine, also called protein based vaccine or recombinant protein-based vaccine. The information is mainly from the National Institute of Allergy and Infectious Diseases (NIAID) of the US National Institute of Health (NIH) and Centers for Disease Control and Prevention (CDC).^2,3

What is a protein subunit vaccine?
A protein subunit vaccine contains harmless pieces of protein from a viral or bacterial pathogen. These fragments of proteins are identified as the best part of the pathogen to produce a strong and effective immune response. Once vaccinated, the protein subunit triggers the immune system in our body to make T-lymphocytes and antibodies that fight against and remember the protein subunit. Later, when there is infection from the real pathogen, the body can recognize the protein subunit on the pathogen and respond quickly to kill the whole pathogen. For the protein subunit vaccines against COVID-19, most of them are either Spike glycoprotein (S protein) on the surface of the SARS-CoV-2, or the receptor-binding domain (RBD) fragment of a region on the S protein that binds to the receptors of a host cell.^2,3

What are the advantages and disadvantages of protein subunit vaccines?
Since protein subunit vaccines include only the components, but not the entire pathogen, this minimizes the risk of side effects. This is best illustrated using of the pertussis (whooping cough) vaccine, which contains components of purified Bordetella pertussis (B. pertussis, the bacteria that cause whooping cough), in 1996. Since the use of the protein subunit vaccine against B. pertussis, to replace the inactivated, whole-cell pertussis vaccines which have been introduced since the 1940s in the United States, the adverse reactions such as fever and swelling at injection site rarely happen. Moreover, the pertussis vaccines containing only protein subunits of B. pertussis have similar efficacy as the traditional inactivated ones.²

However, the precision has its downsides. The protein subunit vaccines most probably do not contain molecular structures called pathogen-associated molecular patterns, which can be read by immune cells and recognized as danger signals. Moreover, the protein subunit may only trigger antibody-mediated immune responses, but not the complete immune responses. Both of these two factors result in an immune response weaker than using the whole-cell vaccines. In order to overcome the problems, protein base vaccines are usually delivered with adjuvants, agents that enhance the immune system. Additionally, booster doses are often required.⁴

Protein subunit vaccines are made by inserting genetic code for the antigen into living organisms such as bacteria and yeast. The whole manufacturing process requires strict hygiene to avoid contamination with other organisms. This makes them more expensive to produce than chemically-synthesised vaccines, such as mRNA or DNA vaccines. The amount of available protein subunit expands as the bacteria or yeast grows. The final protein subunit vaccine contains the protein subunit extracted and purified from the bacteria or yeast, and other vaccine components such as preservatives to keep it stable, plus adjuvant to enhance the immune response. ⁴

Protein subunit vaccines are classical vaccines which are already in widespread use, such as the protein subunit vaccines to prevent hepatitis B and human papillomavirus (HPV) infections, which have been used since 1986 and the early 1990s respectively.⁴ Therefore the technology in developing and manufacturing protein subunit vaccines should be very mature and reliable by now. Moreover, there is no report of serious incident due to this type of vaccine throughout over 30 years of history, showing they are safe.

Below is a list summarizing the advantages and disadvantages of protein subunit vaccines:⁴
1. The technology is well established. It is a reliable and safe vaccine platform.
2. Suitable for people with compromised immune systems, as no live components are involved in the vaccine. No risk of the vaccine triggering the disease.
3. Relatively stable compared to mRNA and DNA vaccines.
4. Relatively complex and expensive to manufacture compared to the synthesized vaccines.
5. Adjuvants and booster shots may be required.
6. Time needs to spend in determining the best antigen combination.

Thus far, there are 23 protein subunit COVID-19 vaccines in clinical trials (out of a total of 70 COVID-19 vaccines in clinical trials); two of them are in Phase 3 clinical trials.⁵ One is by Novavax and the other is by a biopharmaceutical company in China. In my next blog post I’m going to introduce to you the vaccine by Novavax which had an interim report of the Phase 3 clinical study published at the end of last month.⁶



References
1. Coronavirus (COVID-19) vaccine. NHS website. https://www.nhs.uk/conditions/coronavirus-covid-19/coronavirus-vaccination/coronavirus-vaccine/
2. Vaccine types. Subunit vaccines. NIAID website. https://www.niaid.nih.gov/research/vaccine-types.
3. Understanding how COVID-19 vaccines work. CDC website. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/different-vaccines/how-they-work.html
4. What are protein subunit vaccines and how could they be used against COVID-19? Gavi, The Vaccine Alliance website. https://www.gavi.org/vaccineswork/what-are-protein-subunit-vaccines-and-how-could-they-be-used-against-covid-19
5. Draft landscape and tracker of COVID-19 candidate vaccines. WHO. https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines
6. Covid-19: Novavax vaccine shows 89% efficacy in UK trials. BBC News, 29 January, 2021. https://www.bbc.co.uk/news/uk-55850352

About Moderna

About Moderna
Moderna, Inc., is an American biotechnology company based in Cambridge, Massachusetts. It has a fully integrated manufacturing plant and clinical development site in Norwood, MA, which opened in 2018.¹ It went public and was listed on NASDAQ in December 2018 and created the largest biotech initial public offering in history on NASDAQ.² Moderna has been ranked in the top ten of Science’s list of top biopharmaceutical industry employers for the past five years.³

The company was founded in 2010 by three scientists, Derrick J. Rossi, Kenneth Chien and Robert Langer, at Harvard Medical School, and by Flagship Ventures.⁴ Since 2011, Moderna has been led by Stéphane Bancel as the company’s CEO. He is a French businessman with pharmaceutical sales and operations experience.

Since the start of the vaccine race in combating COVID-19, Moderna has been well known for its use of messenger RNA (mRNA) as a vaccine. However, when it was initially founded, it mainly focused on the use of modified mRNA technology to reprogram stem cells for therapeutic purposes,¹ which is the research focus of the one of the co-founders, Professor Derrick Rossi.⁵ The company has changed their direction of interest very quickly since then. Nowadays, Moderna uses its mRNA platform to perform drug discovery and drug development, as well as vaccine development.

The products the company is developing
According to Moderna’s website, aside from the vaccine against the novel coronavirus SARS-CoV-2 (mRNA-1273), the company is also developing 10 other vaccine candidates against infections in three main areas.

1.Vaccines against respiratory infections
• Respiratory syncytial virus (RSV) vaccine for older adults (mRNA-1777 and mRNA-1172)
• RSV vaccine for young children (mRNA-1345)
• Human metapneumovirus and parainfluenza virus type 3 (hMPV/PIV3) vaccine (mRNA-1653)
• Novel coronavirus (SARS-CoV-2) vaccine (mRNA-1273)
• Influenza H7N9 (mRNA-1851)
• H10N8 (mRNA1440)
2. Vaccines against infections transmitted from mother to baby
• Cytomegalovirus (CMV) vaccine (mRNA-1647)
• Zika vaccine (mRNA-1893)
3. Vaccines against highly prevalent viral infections
• Epstein-Barr virus (EBV) vaccine (mRNA-1189)
• Chikungunya virus (mRNA-1944)

Of these, Moderna has 7 vaccine candidates, which are against H10N8,⁶ H7N9,⁶ RSV,⁷ Chikungunya virus,⁸ hMPV/PIV3,⁹ and Zika,¹⁰ currently in Phase 1 clinical studies. The company’s CMV vaccine is even currently in a Phase 2 dose-confirmation study.¹¹

As mentioned earlier in this blog post, Moderna also performs drug development. It is now currently developing therapeutics mRNA for immuno-oncology (mRNA-2416 for advanced/ metastatic solid tumours or lymphoma, Phase 1;¹² mRNA-2752 for relapsed/ refractory solid tumours malignancies or lymphoma, Phase 1¹³), for rare diseases (mRNA-3704 for Methylmalonic Acidemia (MMA),Phase 1/2¹⁴; mRNA-3927 for Propionic Acidemia (PA)¹⁵), and for cardiovascular diseases (mRNA AZD-8601, Phase 2)¹⁶, independently or with strategic collaborators.

Besides the public organizations mentioned in my previous blog post, Moderna has established a wide collaboration network with different biopharmaceutical companies (Merck, AstraZenecca, Alexion, et al.) and research institutions.



References
1. Key milestones and advancements in mRNA technology-Moderna. Moderna. https://www.modernatx.com/about-us/modernas-key-milestones-and-advancements
2. Moderna: 5 things to know about the largest biotech to IPO. MarketWatch, Dec. 7, 2018. https://www.marketwatch.com/story/moderna-ipo-5-things-to-know-about-what-could-be-the-largest-biotech-ipo-in-history-2018-12-05
3. Moderna named top employer by Science for sixth consecutive year. Business Wire, October 30, 2020. https://www.businesswire.com/news/home/20201030005447/en/
4. ModeRNA, stealth startup backed by Flagship, unveils new way to make stem cells. Erin Kutz. Xconomy, 4th Oct., 2010.
5. L. Warren, P.D. Manos, T. Ahfeldt, et al. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell, Volume 7, Issue 5, p.618-630, November 05, 2010.
6. R.A. Feldman, R. Fuhr, I. Smolenov, et al. mRNA vaccines against H10N8 and H7N9 influenza viruses of pandemic potential are immunogenic and well tolerated in healthy adults in Phase 1 randomized clinical trials. Vaccine, Volume 37, Issue 25, 31 May 2019, Pages 3326-3334.
7. Moderna announces updates on Respiratory Syncytial virus (RSV) vaccine program. Moderna press release, October 8, 2020. https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-updates-respiratory-syncytial-virus-rsv/
8. Moderna Announces Positive Phase 1 Results for the First Systemic Messenger RNA Therapeutic Encoding a Secreted Protein (mRNA-1944). Moderna press release, September 12, 2019. https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-positive-phase-1-results-first-systemic/
9. Safety and immunogenicity of mRNA-1653, a combined human Metapneumovirus (hMPV) and Parainfluenza Virus Type 3 (PIV3) Vaccine, in healthy adults, and children 12-36 months of age with serologic evidence of prior exposure. ClinicalTrials.gov. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT04144348
10. Safety, tolerability, and immunogenicity of Zika Vaccine mRNA-1893 in healthy flavivirus seropositive and seronegative adults. Moderna press release, August 19, 2019. https://investors.modernatx.com/news-releases/news-release-details/moderna-receives-fda-fast-track-designation-zika-vaccine-mrna/
11. Moderna completes enrollment of Cytomegalovirus (CMV) Vaccine (mRNA-1647) Phase 2 study. Moderna press release, March 3, 2020. https://investors.modernatx.com/news-releases/news-release-details/moderna-completes-enrollment-cytomegalovirus-cmv-vaccine-mrna/
12. Dose escalation and efficacy study of mRNA 2416 for intratumoral injection alone and in combination with durvalumab for patients with advanced malignancies. ClinicalTrials.com. https://www.clinicaltrials.gov/ct2/show/NCT03323398?term=Moderna&recrs=ab&rank=2
13. Dose escalation study of mRNA-2752 for intratumoral injection to patients with advanced malignancies. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03739931?term=mRNA-2752-P101&rank=1
14. Open label study of mRNA-3704 in patients with isolated Methylmalonic Acidemia. ClinicalTrials.gov. https://www.clinicaltrials.gov/ct2/show/NCT03810690?cond=Methylmalonic+Acidemia
15. "The MaP Study": Mapping the Patient Journey in MMA and PA. ClinicalTrials.gov. https://www.clinicaltrials.gov/ct2/show/NCT03484767
16. Entering a new era in vascular and cardiac regeneration research. AstraZeneca. https://www.astrazeneca.com/what-science-can-do/topics/next-generation-therapeutics/entering-a-new-era-in-vascular-and-cardiac-regeneration-research.html

Coronavirus (34) mRNA vaccine candidate for COVID-19: mRNA-1273 (part b)

Coronavirus (34) mRNA vaccine candidate for COVID-19: mRNA-1273 (part b)
The Moderna COVID-19 vaccine was approved by the UK government on 8th January, 2021. It is the third vaccine against COVID-19 approved to be used in the UK.¹ Guidance from the UK government to health professionals in the use of mRNA-1273 gives us ideas of the details in the use of this vaccine, the safety issues and to whom the vaccine can be given.²

Administration of the COVID-19 Vaccine Moderna
According to the guidance, only people of age 18 years and older are allowed to receive the Moderna vaccine. The injection should be administered intramuscularly, ideally using the deltoid muscle of the upper arm. The vaccination is a two-dose programme, with the doses administered 1 month (28 days) apart.

The vaccine can be shipped and stored for up to 6 months at -20ºC, and then remain stable once thawed for 30 days if refrigerated at between 2ºC and 8ºC. Each vial of vaccine contains 10 doses. Once each vial is thawed and ready to be used, the health professional will withdraw only 0.5ml of vaccine from the vial for injection.

The vaccine is normally white to off-white in colour, and may contain white or translucent product-related particulates. At the time of injection, you can help to check the vaccine by visually inspecting if there is any other particulate matter and/or discolouration. The vaccine should not be used if either of these conditions exist.

Safety issues
From clinical trial studies, it was found that the administration of the vaccine could cause pain at the injection site, fatigue, headache, myalgia (muscle aches or pain), arthralgia (joint pain), chills, nausea/vomiting, axillary swelling/tenderness, fever, swelling at the injection site, and erythema (skin redness) at the injection site. After the two doses of vaccination, the most common solicited adverse reactions included “injection site pain (88.2%), erythema (8.6%), swelling (12.2%), and ipsilateral lymphadenopathy (14.2%)”. Most of these reactions were mild to moderate. However, there was a higher occurrence of severe reactions after the second injection. Most of local reactions occurred within the first day or two after injection and then disappeared.

As events of anaphylaxis (severe, whole-body allergic reactions) have been reported, the guidance suggests health professionals should keep an eye on the patient for at least 15 minutes after vaccination. The guidance also suggests appropriate medical treatment and supervision to manage immediate allergic reactions be readily available in case of an acute anaphylactic reaction following administration of the COVID-19 Vaccine Moderna. Therefore, don’t panic if you suddenly experience an anaphylactic reaction immediately after injection: the vaccination centre should be ready to manage the situation. However, a second dose of the Moderna vaccine would not be given to you if you experienced severe allergic reactions after the first dose.

Precautions
According to the guidance, the following people will not be administered the Moderna COVID-19 Vaccine:
1. Children under 18 years of age;
2. People with severe allergic history;
3. Pregnant women. There is insufficient data to inform vaccine-associated risks in pregnancy. “Administration of COVID-19 Vaccine Moderna in pregnancy should only be considered when the potential benefits outweigh any potential risks for the mother and foetus”;
4. Women during breast-feeding. Data is not available to assess the effects of the Moderna vaccine on the breastfed infant or on milk production/excretion.

The guidance also suggests that health professionals should postpone the vaccination if individuals experience a severe febrile illness or severe acute infection. The jab can be provided to these individuals only when the acute illness has improved.

The guidance also says that “efficacy, safety and immunogenicity have not been assessed in immunocompromised individuals, including those receiving immunosuppressant therapy. The efficacy of COVID-19 Vaccine Moderna may be less in these individuals.” If you are an immunocompromised person, who is also receiving immunosuppressive therapy, you should be bear in mind that you may have a diminished response to the Moderna vaccine, which means the protection you could get from the vaccination would be less than that of other people.

​ The efficacy of the Moderna vaccine is about 94%. Therefore, we have to understand that even if we have been vaccinated with one or two shots of the vaccine, the vaccination does not guarantee full protection. In any case, we should bear in mind that we have to wait at least 14 days after the second dose in order to get the maximum protection from the vaccination.

“The duration of protection afforded by the vaccine is unknown at present.” We may lose protection against the SARS-CoV-2 a certain period of time after the vaccination course. It is important to follow instructions from the government even after the whole nation’s vaccination scheme is completed.



References
1. Moderna becomes third Covid vaccine approved in the UK. By Michelle Roberts. BBC news. 8 January, 2021. https://www.bbc.co.uk/news/health-55586410
2. Regulatory approval of COVID-19 Vaccine Moderna. Regulation 174 Information for UK healthcare professionals. 8th January, 2021. https://www.gov.uk/government/publications/regulatory-approval-of-covid-19-vaccine-moderna