Keeping Pace with MUTATING VIRUSES

A surge in the pandemic has forced the pharma industry to deliver a wide-spectrum vaccine to fight mutation-prone SARS-CoV-2, pledging to prevent future outbreaks. WHO states that the most extensive vaccination campaign in history is providing prophylactic results by delivering more than 12 billion doses of the COVID-19 vaccine, protecting 60 per cent of the global population as of June 2022. Now the next-generation COVID-19 vaccines are countering the challenge of enhancing the immune response to tackle the emerging COVID-19 variants. It is therefore imperative to remain vigilant and upgrade vaccine candidates to emerging virus sublineages. In order to gain a competitive position in the market, vaccine manufacturers are investing in advanced platform technologies. Let’s take a closer look at some of these leading vaccines approved in APAC as broad spectrum virucide inhibitors.

As of July 2022, uncertainty persists as waves of SARS-CoV-2 continue to emerge. Over time, new virus variants arise and threaten to reduce the impact of existing vaccine efforts.

There is a clear need for potential strategies to tackle emerging variants, and to protect populations against the future pandemic.

Over the past 30 months, the development of the vaccine has been a prolonged and arduous process for the biopharma industry across the globe. The companies are investing in large production infrastructures with widespread distribution and are steadfast in bringing the COVID-19 vaccine to market. The global industry stakeholders share next-generation vaccine platforms by leveraging the capabilities and long-standing expertise of innovation to overcome the competitive barriers. An enviable network of alliances has emerged among global firms and a wide range of government and regional commercial partners, and the Asia Pacific (APAC) region is not an exception.

As of July 20, 2022, the World Health

Organisation (WHO) has granted 11 vaccines an Emergency Use Listing (EUL) for global usage. Around 40 vaccines have been approved, authorised, licensed, granted Emergency Use Authorisation (EUA) by at least one country, or made available for use outside of clinical trials via any pathway by a regulatory agency, a national authority, or another entity. As per the records, at least one COVID-19 vaccine of any type has been approved in 197 countries. Further, there are 753 vaccine trials currently active with 220 vaccine candidates in 78 countries.

Dodgy Omicron

Several COVID-19 vaccine candidates currently in use target the receptor-binding domain (RBD) of SARS-CoV2 spike proteins in order to elicit an immune response. In most cases, the new variants of SARS-CoV2 like Delta and other evolving sublineages of Omicron (BA.1. BA.2, BA.4, and BA.5) have outcompeted variants of SARS-CoV2 and its evolving sublineages have outcompeted B.1.1 early variant by evading the immune response induced by the vaccines currently in use. A recent observation indicates that Omicron now accounts for roughly 97 per cent of infections globally, with BA.2 accounting for the greatest share (39 per cent) as a dominant sub-variant. Further, the Omicron variant of COVID-19 is evolving into several more transmissible variants that are rapidly gaining ground.

“Altogether, multiscale investigations suggest that the risk of [L452-bearing Omicron variants], particularly BA.4 and BA.5, to global health is potentially greater than that of original BA.2,” says Kei Sato and colleagues at the University of Tokyo. Another thing that’s concerning some scientists is a mutation in the spike protein gene at position LR452, which may make BA.4 and BA.5 (and related variants, including BA.2.12.1) more contagious than earlier Omicron variants, as well as more prone to infecting lung tissue.

Having identified these emerging pitfalls, regulatory authorities worldwide have advised vaccine companies to update their products with an additional Omicron BA.4/5 component to create bivalent booster vaccines. Companies are not being asked to tweak their existing primary COVID-19 vaccines, as the regulator sees these as providing a ‘base of protection’ against serious outcomes. Nevertheless, biopharma companies and R&D centres are now on their toes to catch the race to compete with the virulence rate and regulatory

“We are on track to fulfil our commitment to deliver at least 2 billion doses to lowand middle-income countries in 2021 and 2022, including at least 1 billion doses this year.” - Dr Albert Bourla, Chairman and Chief Executive Officer, Pfizer

“The data show the ability of our monovalent and bivalent Omicron-adapted vaccine candidates to significantly improve variant-specific antibody neutralisation responses.” - Prof. Ugur Sahin, M.D., CEO and Co-founder, BioNTech

“In the second quarter, we expect to have Omicroncontaining bivalent COVID booster vaccine candidates with robust Phase 3 pipeline leading to three respiratory commercial launches over the next two to three years”. - Stephane Bancel, Chief Executive Officer, Moderna

“We will play a role as a global vaccine hub as an innovative vaccine/ bio partner based on the cooperation with various global companies, as well as developing diverse vaccines independently.” - Jaeyong Ahn, CEO, SK bioscience

“We built a manufacturing infrastructure that has set the stage for widespread distribution of NVX-CoV2373. Today, we are proud to be delivering our COVID-19 vaccine across North America, Europe, Asia, Australia, and Oceania.” - Dr James F. Young, Ph.D. Chairman of the Board of Directors Novavax

pressure.

Meanwhile, regulators at European Medicines Agency (EMA) and the United States of America (USA) Food and Drug Administration (FDA), and Asian regions are advising vaccine makers to update their booster shots for BA.4 and BA.5 variants to remain vigilant. Companies are thoughtfully deploying capital in a variety of shareholder-friendly ways with the goal of maximising the value for all stakeholders, including patients. Here we discuss some of the vaccine candidates approved by the WHO which are claiming promising results to meet global expectations.

Comirnaty (BNT162b2_ mRNA vaccine) [Pfizer and BioNTech]

COMIRNATY is developed by Pfizer using BioNTech’s proprietary mRNA technology platform with BioNTech being the marketing authorisation holder. In the APAC region, COMIRNATY has already been deployed under EUA or equivalent regulatory approvals in most countries.

On June 25, 2022, Pfizer and BioNTech announced positive data evaluating the safety, tolerability, and immunogenicity of two Omicronadapted COVID-19 vaccine candidates: one monovalent and the other bivalent. Preliminary laboratory studies demonstrate both Omicronadapted candidates neutralise Omicron BA.4 and BA.5 though to a lesser extent than they do for BA.1

“Based on the data from the Phase 2/3 trial, we have two very strong Omicron-adapted candidates that elicit a substantially higher immune response against Omicron than we’ve seen to date,” said Dr Albert Bourla, Chairman and Chief Executive Officer, Pfizer.

“The data show the ability of our monovalent and bivalent Omicron-adapted vaccine candidates to significantly improve variant-specific antibody neutralisation responses,” said Prof. Ugur Sahin, M.D., CEO and Co-founder of BioNTech.

On July 8, 2022, COMIRNATY became the first and only COVID-19 vaccine to be granted

FDA approval for adolescents 12 years and older, following EUA in May 2021. Pfizer and BioNTech also filed these data with the EMA and other regulatory authorities worldwide.

Pfizer reported strong financial results and revenue status for the first quarter of 2022, indicating COMIRNATY revenues of approximately $32 billion, which reflects anticipated operational increases offset. This status includes doses expected to be delivered in fiscal 2022 under contracts signed as of mid-April 2022.

First-quarter 2022 operational growth was primarily driven by COMIRNATY globally, which grew from $10.2 billion operationally to $13.2 billion in direct sales and alliance revenues, driven by global uptake including paediatric and booster doses, following a growing number of regulatory approvals and temporary authorisations.

Dr Bourla, stated, “We are on track to fulfil our commitment to deliver at least 2 billion doses to low- and middle-income countries in 2021 and 2022, including at least 1 billion doses this year.”

Meanwhile, for the financial year 2022, BioNTech estimates COVID-19 vaccine revenues of $13.5 billion to $17.5 billion. BioNTech holds 2.4 billion doses of COVID-19 vaccine orders for delivery in 2022.

The company has initiated the expansion of Phase 3 clinical trials to include Omicron-based vaccine candidates.

SPIKEVAX (mRNA-1273 vaccine) [Moderna]

As of July 11, 2022, Moderna unveiled its data on its Omicron-containing bivalent booster candidate mRNA-1273.214, stating that it can elicit neutralising antibody responses 1.69 times higher than the current

“COVAXIN is a multi-epitope vaccine with antibodies against spike, RBD, and N proteins. We have now achieved our goal of developing a safe and efficacious vaccine with longterm protection against a spectrum of variants.” - Dr Krishna Ella, Chairman and Managing Director, Bharat Biotech

“Vaxzevria can help prevent Omicronrelated infections when given as a fourth dose, with greater protection against infection than was seen following a third dose.” - John Perez, Senior Vice President, Head of Late Development, Vaccines & Immune Therapies, AstraZeneca

booster. Moderna announced new clinical data on its bivalent Omicron (BA.1) booster candidate, mRNA1273.214, and completed regulatory submissions in the EU, UK, and Australia.

Moderna, in its multiple Phase 2/3 studies demonstrates superior breadth and durability of the immune response following a bivalent booster. SPIKEVAX (mRNA-1273.214) is reportedly demonstrating significantly higher antibody titers against all tested variants, including Omicron BA.1 and BA.4/5 subvariants, ancestral virus, Alpha,

Beta, Delta, and Gamma compared to the currently authorised booster (mRNA-1273). The company is simultaneously developing mRNA-1273.222, a bivalent candidate based on BA.4/5, as per the latest regulatory guidance. Both bivalent candidates contain 25 μg of the currently authorised booster (mRNA-1273) and 25 μg of an Omicron subvariant.

Stephane Bancel, Chief Executive Officer of Moderna shared, “We are working with regulators to advance two bivalent vaccine candidates, mRNA1273.214 and mRNA-1273.222, based on different market preferences for Omicron subvariants, clinical data requirements”.

Sharing Moderna’s signed advanced purchase agreements for 2022 of $21 billion in Q1 progress, Bancel explains “In the second quarter, we expect to have Omicron-containing bivalent COVID booster vaccine candidates with robust Phase 3 pipeline leading to three respiratory commercial launches over the next two to three years”.

The 2022 financial results at Moderna indicate its total revenue of $6.1 billion for the first quarter of 2022, compared to $1.9 billion for the same period in 2021. Product sales for the first quarter of 2022 were $5.9 billion from sales of the company’s COVID vaccine, compared to $1.7 billion in the first quarter of 2021. Similarly, the cost of sales was $1 billion, or 17 per cent, of product sales for the first quarter of 2022, including third-party royalties of $207 million. Thus, Moderna reported a Net Income of $3.7 billion for the first quarter of 2022, compared to $1.2 billion for the same period in 2021.

Moderna’s 2022 Advanced Purchase Agreements (APAs) for product sales are approximately $21 billion and the company believes that COVID market dynamics will result in sales slightly larger in the second half of 2022 than in the first half.

Furthermore, Moderna announced a strategic partnership with the Australian Federal Government to establish a state-of-the-art, domestic mRNA vaccine manufacturing facility in Australia.

Simultaneously, Moderna announced its Global Public Health Strategy through four new initiatives aimed at advancing mRNA vaccines for the prevention of infectious diseases, including a new program, mRNA Access, that will allow researchers to use Moderna’s mRNA technology to explore new vaccines against emerging or neglected infectious disease.

GEMCOVAC-19_(mRNA vaccine) [Gennova Biopharmaceuticals]

India-based Gennova Biopharmaceuticals, a subsidiary of Emcure Pharmaceuticals in collaboration with HDT Bio Corp, has introduced its mRNA vaccine GEMCOVAC-19 which has received the EUA from the office of the Drugs Controller General of India (DCGI). With this in June 2022, GEMCOVAC-19 became the world’s third mRNA vaccine and the first mRNA vaccine to be developed in India, approved and available for administration. GEMCOVAC-19 is a Lyophilised mRNA vaccine for Injection.

Gennova Biopharmaceuticals aims to produce around 40-50 lakhs doses per month, potentially doubling this capacity quickly. Gennova aims at providing sustainable access to low-and middleincome countries around the world to the vaccine to blunt the spread of pandemics.

VAXZEVRIA / COVISHIELD_(ChAdOx1-S [Recombinant]) AstraZeneca (formerly known as AZD1222)

According to new data from Thailand’s Chiang Mai University, AstraZeneca’s Vaxzevria (ChAdOx1-S

[Recombinant]) ‘viral vector’ vaccine is proven to be effective against the Omicron variant when used as a fourth dose booster. Based on the data, John Perez, Senior Vice President, Head of Late Development, Vaccines & Immune Therapies, AstraZeneca, said, “Vaxzevria can help prevent Omicron-related infections when given as a fourth dose, with greater protection against infection than was seen following a third dose.”

Vaxzevria has been granted a conditional marketing authorisation or emergency use in more than 125 countries. It also has EUL from the WHO, which accelerates the pathway to access in up to 144 countries through the COVAX Facility. Under a sublicense agreement with AstraZeneca, the vaccine is manufactured and supplied by the Serum Institute of India under the trade name COVISHIELD.

Sharing the Q4 (fourth quarter) 2021 financial reports the company noted that it has delivered approximately 102 million doses of its COVID-19 vaccine through COVAX. As of the end of December 2021, the company and its sublicensee Serum Institute of India Pvt. Ltd. (SII) has delivered more than 247 million doses with COVAX to 130 countries. As of February 2022, AstraZeneca and SII remain the largest contributor to COVAX and have released more than 2.8 billion vaccine doses to over 180 countries, two-thirds of which are in low- and middle-income countries.

Further, in its Q1 2022 financial statements released on April 29, 2022, the company indicates its financial performance (growth numbers at CER) with an increase in Total Revenue by 60 per cent to $11,390 million, reflecting growth across the company, including several Vaxzevria contracts that are expected to complete the delivery by half year 2022. In its Q4 2021 financial statements, AstraZeneca indicates Total Revenue increased by 41 per cent (38 per cent at CER1) to $37,417 million including COVID-19 vaccine revenues.

The majority of Vaxzevria revenue in 2022 is expected to come from initial contracts. Thereafter, AstraZeneca expects a decline in its COVID-19 vaccine revenues due to a projected decline in Vaxzevria sales partially offset by an increase in its Evusheld COVID-19 medicine sales.

Meanwhile, on January 13, 2022, the company announced that COVISHIELD as the third dose of booster vaccine is found to be effective against Beta, Delta, Alpha, and Gamma strains of SARS-CoV 2.

COVOVAX / Nuvaxovid (NVX-CoV2373 protein-based vaccine)_Novavax

NVX-CoV2373 is a protein-based vaccine candidate developed using a proprietary recombinant technology platform harnessing highly immunogenic nanoparticles in the form of the NVX-CoV2373 COVID-19 vaccine. Novavax’s recombinant protein nanoparticle COVID-19 vaccine uses Matrix-M as an adjuvant. Serum Institute of India Pvt. Ltd. markets NVX-CoV2373 under the brand name Covovax SARSCoV-2 rS Protein Nanoparticle [Recombinant]). Covovax has received EUL from the WHO, as well as EUA in India, Indonesia, the Philippines, Thailand, and Bangladesh.

However, in Europe and non-APAC markets the vaccine is marketed by Novavax with the trade name Nuvaxovid COVID-19 Vaccine (SARS-CoV-2 rS [Recombinant, adjuvanted]). Nuvaxovid is approved in 39 countries and undergoing 17 trials in 13 countries as stated by WHO. Novavax and SII have committed a cumulative 1.1 billion doses of the Novavax vaccine to COVAX.

On July 13, 2022 Novavax announced that the Novavax COVID-19 Vaccine, Adjuvanted (NVXCoV2373) has received EUA from the US FDA to provide a two-dose primary series for active immunisation. Novavax already has BA.1 and BA.4 and BA.5 monovalent vaccines in development, with results expected in Q3 and Q4 2022.

“We built a manufacturing infrastructure that has set the stage for widespread distribution of NVXCoV2373. Today, we are proud to be delivering our COVID-19 vaccine across North America, Europe, Asia, Australia, and Oceania” Dr James F. Young, Ph.D. Chairman of the Board of Directors Novavax.

COVAXIN_(whole-virion inactivated vaccine) [Bharat Biotech]

COVAXIN, India’s indigenous COVID-19 vaccine, a whole-virion inactivated COVID-19 vaccine candidate by Bharat Biotech is developed using a Whole-Virion Inactivated Vero Cell-derived platform technology, in collaboration with the Indian Council of Medical Research (ICMR) - National Institute of Virology (NIV).

On July 20, 2022, the company indicated that COVAXIN demonstrated persistent immunogenicity against spike protein, N protein, and neutralising antibody responses against emerging variants (Alpha, Beta, Delta, Delta Plus, and Omicron) and showed increased memory B cell response. On April 26,

2022, BBV152 (COVAXIN) received emergency use approval in children 6-12 years.

Dr Krishna Ella, Chairman and Managing Director, Bharat Biotech, said, “COVAXIN is a multiepitope vaccine with antibodies against spike, RBD, and N proteins. A post booster dose has proven to

neutralise antibody responses against variants of concern and long-term protection through memory T and B cell responses. We have now achieved our goal of developing a safe and efficacious vaccine with longterm protection against a spectrum of variants.”

Future trends

In June 2022, the World Trade Organisation (WTO) adopted a waiver of the Agreement on Trade-Related Aspects of IP Rights (TRIPS Agreement) for COVID-19-related vaccines and pharmaceuticals. With the waiving of the TRIPS Agreement, many governments hope to benefit from obtaining a vaccine platform and formulation, along with knowledge sharing which is expected to enhance mass production without any compensation to the original developer. Many predict that this would have massive consequences for the expected return on investment of life sciences companies developing these products. International experts opine that the waiver will harm innovation and may lead to the overproduction of vaccines and wastage of formulation components. There is a need to accelerate research and development into nextgeneration vaccines, tests, and treatments from all stakeholders.