Covid-19: Vaccine Development

Cover Story COVID-19 - Vaccine Development

COVID-19 VACCINE DEVELOPMENT CHALLENGES GALORE

Prof. Dr. D M Vasudevan,

MBBS, MD (Biochem), FRCPath, Technical Director, AGAPPE In December 2019, a new disease, named as Covid-19 (abbreviation of Corona virus Disease 2019) emerged from Wuhan, China. It has been recognized as a pandemic by WHO, affecting almost all the countries of the world. The first case of the disease was reported in India from Kerala on 30 January 2020. This article presents an overview of this pandemic and discusses the various preventive measures and treatment procedures besides providing an update on the hectic efforts to find a vaccine for Covid-19.

The world continues to be under the grip of the Covid 19 pandemic even as efforts to develop an effective vaccine to fight the disease are on a fast track. However, the challenges to bring out a safe vaccine after proper clinical trials are many. However, such a vaccine is well on the way if the encouraging reports of the ongoing efforts by various countries and organizations are any indication.

A new type of pneumonia was detected in the Wuhan Province of China, in December 2019 and the disease was named as Coronavirus 2019 (Covid-19). The virus producing this dis

ease is named as Sars-CoV-2. The disease is a pandemic affecting all countries of the world. Since there are no effective drugs available, developing an effective vaccine to fight the new disease could be our only ray of hope.

As on the last week of August 2020, there are 231 vaccines under various stages of development. About 19 are in phase 1 and 2 clinical trials, while 6 are in phase 3 trial. However, till the end of August, no vaccine has completed clinical trials. Of the candidate vaccines, about 70% are being developed by private companies, with the remaining projects under development by academic, government coalitions, and health organizations. It is hoped that vaccine may be available for the general public by the end of this year. Previous works to develop a vaccine against the coronavirus diseases (SARS and MERS) established considerable knowledge about the structure and function of coronaviruses. Further the genetic sequence of the Covid-19 virus was published in January 2020, which hastened the development of a vaccine.

Technology Platforms

Ten different technology platforms are available to produce vaccine against Covid19. These are

based on DNA, messenger RNA, non-replicating viral vectors, peptides, and recombinant proteins, A vaccine for an infectious live attenuated viruses, and inactivated viruses. When a vaccine is disease will usually take injected, a harmless virus or a many years to develop, as part of that organism is introduced into the body. The body’s defence it has to undergo various system (known as immunologistages. The preclinical cal system) recognises the invader and learns how to fight study or the challenge them. After a few months, when study begins by testing a the natural virus enters, the body already knows how to fight it, and so virus could not produce the vaccine candidate for immunogenicity and safety disease or it could generate only a mild disease. The main method of vaccination for decades has been to use in laboratory animals. If the animal studies are promising, then human studies the original virus. For example, can be started. the measles, mumps and rubella (MMR) vaccine is made by using weakened viruses that cannot cause a full-blown infection. Chinese scientists mainly adopted man studies should undergo phases 1, 2 and 3 in that sequence. this approach. Because the genetic background of the new coronavirus, Sars-CoV-2 is already known, the researchers from Oxford have put small sections of its genetic material into a harmless virus that only infects chimpanzees. This is a safe virus that looks enough like the coronavirus to produce an immune response. Other groups are using pieces of genetic material (either DNA or RNA) which once injected into the body, should start producing bits of viral proteins which the immune system can learn to fight. The phase 1 trials test safety and dosage in 10-15 healthy subjects. Following success in Phase 1, the phase 2 starts in a few hundred people, where dose levels and adverse effects of the candidate vaccine are studied. Phase 2 trials are typically randomized, placebo-controlled. If these tests are promising, the study proceeds to understand the effective dose into a large-scale Phase 3 trial in previously-uninfected, volunteers (young adults), who would then be deliberately infected with The Challenges Aplenty Covid19 for comparison with a placebo control group. Phase A vaccine for an infectious disease will usually take many years to develop, as it has to undergo various stages. The preclinical study or the challenge study begins by testing a vaccine candidate 3 trials will determine the effectiveness of the vaccine to prevent the disease while monitoring for adverse effects. Optimal dose is also studied. for immunogenicity and safety in laboratory animals. If the animal The World Health Organization has established guidelines studies are promising, then human studies can be started. Hufor conducting Covid19 vaccine studies in healthy people, including scientific and ethical evaluation, informed consent of the participants, and monitoring by independent experts. The World Health Organization Many vaccine candidates in preclinical development will not gain approval for human studies due to toxicity or ineffechas established guidelines for tiveness to induce immune responses in laboratory animals. conducting Covid19 vaccine stuThe probability of success for an infectious disease vaccine candidate to pass preclinical barriers and reach Phase 1 of dies in healthy people, including human testing is only 50%. The success rate of obtaining apscientific and ethical evaluation, proval for Phase 3 trial was only 10% for vaccines. informed consent of the participants, and monitoring by indepeDuring the development process, various parameters such as the efficacy and toxicity of the vaccine, the duration of vaccination protection, route of vaccination (such as oral, ndent experts. nasal, subcutaneous, intramuscular), dose regimen, and storage characteristics, optimal manufacturing for scaling to billions of doses, and dissemination of the licensed vaccine are

Cover Story COVID-19 - Vaccine Development

to be studied. Further, population subgroups, such as the elderly, children, pregnant women, and people with existing weakened immune system are to be carefully evaluated.

Host-related determinants that render a vaccine ineffective are genetics, underlying diseases, malnutrition, elderly (above age 65) and hypersensitivity. These persons may require separate vaccine technologies or repetitive booster vaccinations. Further, mutations of the virus can alter its structure targeted by the vaccine, thus making the vaccine ineffective. Compressed Timelines

In the haste to provide a vaccine, governments are under pressure to accept a high risk for the vaccine development process. In the case of Covid19, a vaccine efficacy of 70% may be enough to stop the pandemic. An efficacy of less than 60% will not provide enough herd immunity to stop the spread of the virus alone. Vaccine trials take a long time to develop before they are approved for use. Any vaccine which reaches us at this point would carry a certain level of ambiguity and a risk of danger. Much like the controversy that the Russian vaccine (Sputnik V) finds right now, an expedited vaccine approval would mean that there may be many side-effects when introduced to public consumption. Funding Issues

In July 2020, the WHO announced that 165 countries, representing up to 60% of the world population, had agreed to a WHOCOVAX plan for fair and equitable distribution of an eventual

licensed vaccine. The Coalition for Epidemic Preparedness Innovations (CEPI) further agreed to create US$ 8 billion fund to support research on 3 candidate vaccines. The Bill Gates Foundation is donating US$ 250 million in support of Covid19 vaccines. In June 2020, a summit was coordinated among governments of 52 countries, to raise US$ 8 billion to prepare an effective Covid19 vaccine. Status of Covid Vaccines

As of June 2020, six Covid19 vaccine candidates, developed by Chinese organizations are in early-stage human testing. Other promising vaccines are being studied at Pasteur Institute (France), Themis Bioscience (Austria), and CureVac (Germany). Vaccine development is also progressing within various companies such as Moderna, Johnson & Johnson, and Sanofi in USA. The Moderna vaccine is now in phase 3 clinical trials. Large pharmaceutical companies with experience in making vaccines, including Johnson & Johnson, Astra-Zeneca, and Glaxo-Smith-Kline (GSK), are forming alliances with governments and universities to accelerate progression to an effective vaccine.

Russia, became the first country to grant regulatory approval to a Covid-19 vaccine, (Sputnik V, formerly known as Gam-CovidVac developed by the Gamaleya Research Institute in Moscow. After this announcement, experts have raised considerable concern about the safety and efficacy of the vaccine, as it has not yet entered Phase 3 clinical trials.

Israel Institute for Biological Research (IIBR) has developed a vaccine found to be effective in animal models. This vaccine is developed on vesicular stomatitis virus (VSV) (an animal virus that does not cause disease in humans), and in which the spike protein was replaced with that of Covid virus. This vaccine is called recombinant-VSV-G-spike. Now they are beginning human trials for the vaccine candidate they developed. Israel is expected to have safe and effective vaccines by the end of the first quarter of 2021.

Indian scenario

In June 2020, the Serum Institute of India (SII) reached a licensing agreement with Oxford-Astra

Zeneca to make 1 billion doses of vaccine for low-and-middle income countries including India. This vaccine has been developed by the University of Oxford (Imperial College of London) and distributed by the company Astra-Zeneca. The vaccine is now in phase 3 of clinical trials. The Oxford vaccine will be marketed as ‘Covishield’ in India. This phase 3 trials of the Oxford vaccine was started by the middle of August 2020 in India. About hundred people have been already vaccinated.

The clinical trials will be conducted in 20 centres in In- dia and 1600 persons will be injected. Those who have not been infected by the virus would likely be the first ones to get vaccinated. The healthcare workers and front-line workers should be given priority as initial vaccine candidates. The first batch of doses will be ready for deployment as early as December 2020.

Three Indian vaccines are in different stages of development. Oxford vaccine has already been described. Other locally developed vaccines, Bharat BioTech’s Covaxin and Zydus Cadila’s ZyCOV-D, have entered in clinical trials in the month of July 2020. They are showing promising results. WHO Solidarity Trial

The WHO, with a multinational coalition of vaccine scientists, has developed the Global Target Product Profile (TPP), identifying attributes of safe and effective vaccines. The WHO vaccine coalition will prioritize which vaccines should go into Phase 3 clinical trials, and also to implement Phase 3 protocols for all vaccines. This will avoid duplication of research efforts, across its interna

A vaccine would normally take years, if not decades, to develop. Regarding the Covid infection, researchers hope to achieve the same amount of work within a few months. It is not yet known if it is possible to create a safe, reliable and affordable vaccine for this virus. It is possible that billions of dollars could be invested without any success.

tional locations. Experts emphasize that licensed vaccines should be available and affordable for people at the frontline of healthcare and having the greatest need.

As the elderly or impoverished people are at greater risk, they also get preferential availability for the vaccine. Nonspecific vaccines Assertions have been made that Covid19 mortality has been lower in countries having routine BCG vaccine administered against tuberculosis.

But the World Health Organization (WHO) has not accepted this claim. In March 2020, a randomized trial of BCG vaccine began in the Netherlands, recruiting 1,000 healthcare workers, and another randomized trial in Australia enrolling 4,170 healthcare workers. Such works are going on in Columbia, Brazil, France, Greece and South Africa. In June 2020, a randomized placebo-controlled trial to test whether the measlesmumps-rubella vaccine (MMR) can protect healthcare workers from Covid19 began in Egypt. When Will We Have the Vaccine?

A vaccine would normally take years, if not decades, to develop. Regarding the Covid infection, researchers hope to achieve the same amount of work within a few months. It is not yet known if it is possible to create a safe, reliable and affordable vaccine for this virus. It is possible that billions of dollars could be invested without any success.

Similar to the development of the first polio vaccine that was never patented, an effective Covid-19 vaccine would be available for production and approval by a number of countries and pharmaceutical manufacturing centers worldwide, thereby allowing for a more even and cost-effective distribution on a global scale.

Most experts hope that a vaccine is likely to become widely available by mid-2021, about 12-18 months after the new virus first emerged.