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Phase III trials of Sputnik V critical to know safety and efficacy: Lalit Kant

Covid-19 pandemic is spreading globally like a wild fire in dry leaves. Vaccine offers the only hope for its containment and prevention. So far, millions of dollars have been invested in fast tracking the development of vaccines and telescoping the duration of clinical trials from years to months.
While the top pharma companies across the world are hopeful to come up with a vaccine by the year end, Russia in August announced the launch of Sputnik V, its home brewed adenovirus-based vaccine candidate against covid-19, for the citizens. India too has decided to take the Russian vaccine after clinical trials on Indians.
Lalit Kant, Infectious Disease Epidemiologist and former head of epidemiology and communicable diseases at the Indian Council of Medical Research (ICMR) spoke about why Phase III clinical trials are important for Russian Vaccine, adenovirus vector vehicle of the vaccine, advantages for India and way forward. Edited excerpts from an interview:
What do you think about the safety of Russian covid-19 vaccine Sputnik V?
This is the first covid-19 vaccine approved anywhere in the world. It is reported that the vaccine is now available to public in Moscow. Scientists and health agencies have cautioned against the euphoria as the vaccine has been approved without the results of Phase I/II trial being made public nor the Phase III trial being conducted. Phase III trials are critical to know the safety and efficacy of the vaccine.
Russia’s level of confidence can be gauged by the fact that they are not asking for full indemnity of legal risks from the countries which have shown interest to use their vaccine. This is very unlike what the other manufacturers are seeking – full indemnity, that is complete protection from any future liability claims arising from adverse reactions, with the countries they have signed supply deals. Whether the vaccine would turn out to be a Sputnik moment or a Russian roulette, results of Phase III will tell.
Kindly explain adenovirus vectors on which the Russian Vaccine is based?
The Russian vaccine uses the adenovirus (commonly causes common cold in children) as a vehicle to transport the Adenovirus vector carries S gene that encodes for ‘spike protein’ of the SARS CoV2 to the human body. The adenovirus slips into cells and unloads the gene cargo. It uses a prime boost strategy, that is the vaccine is administered in two doses 21 days apart.
Research on using adenoviruses for carrying foreign genetic material is being perfected since 1980s. The advantage of using adenovirus vectors is that the vector has surface proteins that help facilitate the delivery of the SARS-CoV-2 nucleic acid into the host cell, which then transcribes it to become viral antigens. Adenoviruses have been isolated from humans, simians (monkeys) and birds. Human adenoviruses have more than 50 serotypes and Ad5 is the commonest.
Since adenoviruses are present all over the world and almost all of us would have been exposed to it during our childhood, we all have immunity to it. This pre-existing immunity has been one of the main reasons why adenoviral platforms have had very limited success so far. The only successful application of this strategy has resulted in development and approval of a rabies vaccine for use in animals. Though great efforts have been made for developing a vaccine for HIV, malaria, tuberculosis, Ebola, and Zika virus. To overcome the problem of pre-existing immunity several approaches have been used, like using adenoviruses isolated from Chimpanzees for which humans may have no immunity, giving vaccine in two doses and for each a different serotype of adenovirus is used, and one of them could be common like Ad5 and the other uncommon serotype like Ad26 and Ad35, or using a totally uncommon serotype.
The adenovirus has also been genetically altered and some of its own genes have been stripped off and is therefore unable to replicate and hence minimize reactions with pre-existing immunity. Several companies are using the adenoviral platform for Covid-19 vaccines and some of them are in late stage clinical development for example.
UK’s AstraZeneca uses chimpanzee adenovirus, USA’s Johnson and Johnson’s vaccine is Ad26 based, and Chinese CanSino Biologics is using Ad5 as vector. The Russian vaccine uses Ad5 and Ad26 serotypes for its prime and boost strategy. These vaccines aim to stimulate both arms of the immune system — antibody and T cell responses — so they attack the virus when it is circulating in the body, and also attack cells infected by SARS-CoV-2.
Many countries including India are considering emergency authorisation of covid vaccines. Why do you think Phase III clinical trials are important for any country?
For a vaccine to be pre-qualified for global use by World Health Organization (WHO) it requires data for all three phases of clinical trial (Phase I-III) for review, though each country could have its own criteria for approval in its country. At the time when the Russian vaccine was approved by its national authorities, it had data for Phase I/II and none had been published. Since its publication in the Lancet, scientists have been raising red flag as they observed ‘strange duplicated patterns in the data, among different groups observing different groups’ and have called for re-review of the raw data.
Since its approval in August, phase III trials of the Sputnik V vaccine have started in Russia, there are reports that about 14% of 300 volunteers who received the vaccine have had mild self limiting side-effects (weakness, muscle pain and rise in temperature and chills). The trial is in 40,000 volunteers and results are expected by end of October, 2020.
Immune response seen in Phase I/II of Russian vaccine trial may not be proportional to the degree of protection that is studied in only Phase III.
India will also conduct clinical trials of the Sputnik vaccine on its population. What is your opinion on side effects of the Russian vaccine during already done clinical trials?
If for some reasons Sputnik does not work or results in some kind of unforeseen adverse event(s) in Phase III that could affect public perception of vaccine process. An inefficient product could worsen the pandemic, as those who receive the vaccine may stop taking precautions. Confidence may be dampened by vaccine which received approval and then shown to be harmful. Safety is of paramount importance as the vaccine is being given to healthy individuals and needs to be balanced against risk of infection. A vaccine that reduces the severity of the disease but does not prevent infection might make things worse.
What are the advantages of the Russian Vaccine for India?
One of the formulations of the Russian vaccine is lyophilized. To my mind this is the greatest advantage it offers. Benefits of lyophilized products include reduced refrigerated warehouse requirements, lower shipping costs, simplified product use, and longer shelf life. This formulation could be used within the existing refrigerated cold chain in India, the product stability would maximize reach in remote areas – which will help universal and equitable coverage. Brazil, Cuba, the Philippines, United Arab Emirates and Saudi Arabia have agreed to do a Phase III clinical trial.
On 16 September Dr Reddy’s Laboratory, Hyderabad announced that it had signed an agreement with Russia Direct Investment Fund (RDIF) to conduct Phase III trails of the Sputnik vaccine. Russia is reported to have submitted comprehensive data on vaccine safety and immunogenicity / efficacy to India. If all goes well this might happen before the end of 2020. About 100 million doses will be available for use in Indian population soon thereafter. If the Phase III trials starts in September, it would be the first vaccine to enter Phase III in India, and may become the first vaccine to be licensed for use. If the vaccine candidate is fast tracked and granted emergency authorization, it may well become available earlier.

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