Russia registering a vaccine for novel coronavirus even before beginning a Phase-3 trial and promising to  begin full-scale production of the vaccine in September to make it available by November is riddled with safety and ethical issues. But virologist Dr Jacob John feels a vaccine using a recombinant adenovirus construct to ferry the synthetic genetic material of the virus is well proven and safety is not much of an issue.

In January 2019, the World Health Organization listed ‘vaccine hesitancy’ among the top ten threats to global health that year. It defined vaccine hesitancy as “reluctance or refusal to vaccinate despite the availability of vaccines”. Vaccine hesitancy is best exemplified in the case of Sanofi’s dengue vaccine (Dengvaxia).

Dengue has four serotypes and anyone who is infected for the second time by a different serotype is likely to experience more than six-fold higher risk of severe disease compared with those being infected for the first time. This is due to antibody-dependent enhancement.

Dengue vaccine fiasco

Dengvaxia took more than 20 years and $1 billion to develop. The vaccine was commercialised after undergoing complete clinical trials in humans. The WHO approved its use in April of 2016.

In 2016, Philippines was the first country to begin vaccinating over 0.8 million children with the dengue vaccine. But post vaccination, those who had no prior infection with the virus came down with severe illness when they were exposed to the virus. The vaccine was priming the immune system just like the first natural infection, leaving the person exposed to greater risk of severe disease when infected post vaccination. Philippines soon withdrew the vaccine.

Sanofi revised its label to say: “For individuals who have not been previously infected by dengue virus, vaccination should not be recommended.” But the warning from Sanofi came too late as the trust that people reposed on vaccines was completely shattered. This led to vaccine hesitancy in Philippines leading to low vaccine uptake of other well proven vaccines causing measles and polio outbreaks in the country.

In Samoa, an error in preparing the measles, mumps, and rubella (MMR) injection led to death of two infants. Fear mongering following this led to a sharp drop in vaccine uptake leading to measles outbreak.

Russian misadventure?

Now compare this with the Russia’s Sputnik V vaccine for novel coronavirus, which has been tested only on 18 participants in Phase-1 and 20 participants in Phase-2 trials in June. But the vaccine is set to be available for public use in the coming weeks even before it can be tested on thousands of volunteers in a phase-3 trial and the long-term effects and safety of the vaccine is known. The Phase-3 trial is set to begin shortly but the vaccine has already been registered on August 11.

No data on vaccine safety and efficacy has been made available in any public database. On August 11, scant details about the vaccine was posted by Gamaleya National Research Center, which developed the vaccine, on a website. According to the website, “Phase 1 and 2 clinical trials of the vaccine have been completed on August 1, 2020. All the volunteers are feeling well, no unforeseen or unwanted side effects were observed. The vaccine induced strong antibody and cellular immune response. Not a single participant of the current clinical trials got infected with COVID-19 after being administered with the vaccine. The high efficacy of the vaccine was confirmed by high precision tests for antibodies in the blood serum of volunteers (including an analysis for antibodies that neutralize the coronavirus), as well as the ability of the immune cells of the volunteers to activate in response to the spike S protein of the coronavirus, which indicates the formation of both antibody and cellular immune vaccine response.”

The plan is to carry out a Phase 3 trial from August 12 in more than 2,000 people in Russia as well as other countries such as the United Arab Emirates, Saudi Arabia, Brazil and Mexico.

The vaccine, developed by the Gamaleya National Research Center, has officially been registered with Russia’s Health Ministry. “As far as I know, a vaccine against a new coronavirus infection has been registered this morning, for the first time in the world,” Russian President Vladimir Putin  said at a meeting with members of the government, RIA Novosti reported.

“Although I know that it works quite effectively, it forms a stable immunity and, I repeat, has passed all the necessary checks,” Putin said.

Russia said its work in recent years on developing a vaccine for Ebola and Middle East Respiratory Syndrome (MERS) had helped it to create a vaccine against the new coronavirus. In the case of Ebola vaccine, Russia had a licensed a two-dose vaccine “for emergency use”.  China too had licensed one such vaccine for Ebola for emergency use, says WHO. While the vaccine from China is a single-dose, the Russian vaccine is a two-dose vaccine meant exclusively for “emergency use”. According to the WHO, Ebola vaccines licensed by China and Russia for emergency use were “tested in animal models and data on human immunogenicity from Phase-1 and 2 clinical trials, which included studies in African populations”.

“We were just fortunate that the coronavirus was very close to MERS, so we pretty much had a ready-to-go vaccine on MERS, studied for two years on MERS (and) slightly modified to be the coronavirus vaccine, and that is the real story, no politics … Russia has always been at the forefront of vaccine research,” Kirill Dmitriev, CEO of Russia’s sovereign wealth fund RDIF, which is backing the vaccine, told CNBC.

According to RDIF, full-scale production of the vaccine is expected to begin in September and the vaccine could be available by November.

“We are in close contact with the Russian health authorities, and discussions are going on with respect to possible pre-qualification of the vaccine,” WHO spokesman Tarik Jasarevic told a U.N. briefing in Geneva, Reuters says. “Pre-qualification of any vaccine needs rigorous review and assessment.”

Ethical minefield

Unlike drugs used treating diseases or conditions, vaccines are seen as public good as they are given to healthy people to prevent an infection. Ethics therefore demand that safety and efficacy of vaccines are thoroughly studied and vaccines must necessarily pass a high safety bar. While Phase-1, carried out on a few dozen individuals tests mainly for safety and also looks at immune responses, Phase-2 studies the safety of the vaccine, immune responses and the best and effective dosages and number of doses. Long term safety and efficacy of the vaccine is tested during a Phase-3 trial that is carried out on thousands of volunteers, who are followed up for several months.

The number of participants recruited in Phase-1 and Phase-2 human clinical trials don’t have the statistical power to determine the safety and effectiveness of the vaccine at the population level. This makes Phase-3 all the more important before even applying for regulatory approval. There have been many instances when vaccines that have shown promise in the early phase of human clinical trials but have turned out to be duds at Phase-3 trials.

Skipping Phase-3 trials or making the vaccine available to the public even as the Phase-3 trial is being carried out, as will be the case with Sputnik V vaccine, is not only a dangerous idea but also highly unethical. It puts people at grave risk and at the same time undermines the trust that people repose on vaccines. Pushing the vaccine even before safety and efficacy is proven can be hugely counterproductive and can cause more harm than good.

Vaccine hesitancy

Already, the rush to develop a vaccine against novel coronavirus has eroded the trust in vaccines. Even among those who believe and trust in vaccine science and development are hesitant to get immunised mainly due to the unprecedented short timelines in developing and testing the vaccines in humans.

Never before have vaccines developed from scratch, tested on animals and gone on to Phase-3 trials all under seven months. While a section of the society is eagerly waiting for a safe and effective vaccine to become available at the earliest, there are people who are turning their backs to a rushed-up vaccine.

For instance, Prof. Florian Krammer from the Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York City tweeted: “Not sure what Russia is up to but I certainly would not take a vaccine that hasn’t been tested in Phase III. Nobody knows if its safe or if it works.”

About seven in 10 Americans say they would not get a vaccine to protect against the novel coronavirus even if immunisations are free and available to everyone, according to a Washington Post-ABC News poll.

In the absence of safety and efficacy data in the public domain and no publication of results of Phase-1-2 trials, who and how many in Russia and other countries will be willing to voluntarily get vaccinated? Will the vaccine be made available to military, and government employees who might have very little freedom to refuse vaccines?

Consent by everyone who is getting vaccinated will be necessary as it is still an experimental vaccine, whose safety and efficacy is yet to be proven. But even if people willingly consent to getting vaccinated, there is a serious possibility of erosion of trust in vaccines if the vaccine indeed has serious safety issues.

Safety may not be an issue?

The Sputnik V vaccine is constructed using a recombinant adenovirus (common cold-causing virus) that would ferry the genes of the spike protein. The genes used will be synthetically produced. “The safety of adenovirus is well known. So I don’t see any safety issue by making the vaccines available to public even before Phase-3 trials can be conducted,” says virologist Dr Jacob John from Vellore, Tamil Nadu. “The safety of the vaccine in people with HIV and other conditions need to be studied, which can be done during the Phase-3 trial.”

The Ebola vaccine by Johnson & Johnson approved in June is the first adenovirus vaccine that has completed all phases of human clinical trial and approved by regulatory agencies. Even COVID-19 vaccines by Oxford and Johnson & Johnson use an adenovirus construct to carry the coronavirus genetic material.

Incidentally, on June 25 China approved the use of its recombinant adenovirus candidate vaccine (Ad5-nCoV) for use exclusively by the military for one year. The Chinese approval was based on limited safety and efficacy results from Phase-1 and Phase-2 trials. The Phase-3 trial to test the efficacy and safety of the vaccine on a large number of participants is yet to begin; Phase-3 trial is set to soon begin in Saudi Arabia as circulation of the virus has contained in China. The vaccine was jointly developed by the Beijing Institute of Biotechnology — part of the Chinese government’s Academy of Military Medical Sciences — and vaccine company CanSino Biologics.

Dr Bhan says that besides safety, efficacy of the vaccine is also important. Even if safety of recombinant adenovirus virus has been well studied, making the vaccine available to the public before the completion of Phase-3 trial runs counter to well established norms of clinical trials. “Look how quickly thousands of participants were recruited for the RECOVERY trial in the UK and WHO’s Solidarity Trial. So conducting a Phase-3 trial and waiting for at least the interim results should not take much time,” Dr Bhan says.

Dr Giridhara Babu, epidemiologist at the Public Health Foundation of India, Bengaluru sees an opportunity for India. “India should actually procure vaccine doses from Russia and conduct a large Phase-3 trial in India. If the results are encouraging then we should also look at the prospect of manufacturing it in India and making them available for immunisation.” But if India were to seriously consider this option it should seek the safety and efficacy data of Phase-1 and Phase-2 from Russia and begin with a Phase-2 trial, provided the vaccine is found to be safe in the Russian trials.

According to Reuters, Philippine has already evinced interest in conducting clinical trials and access to research data.

The big vaccine race

Besides politics, Russia sees it a race and wants to claim credit for being the first country to make a COVID-19 vaccine available for public use, says Dr Anant Bhan, a researcher in global health and bioethics.

Prof. Peter Hotez, vaccine scientist at the Baylor College of Medicine’s National School of Tropical Medicine fear such vaccine race in the current atmosphere in the U.S. In a tweet he says: “Still another worry is that the White House will see this as an “arms race” of sorts and use it as an excuse to try and push an Operation Warp Speed Vaccine ahead of the fall election.”

Prof. Hotez is also worried of Russia exporting the little studied vaccine to old-friend countries. He says in a tweet: “My other worry is that the Russians will export a vaccine that is either untested or under tested to countries in Africa or in Latin America — Cuba, Nicaragua, Venezuela — as a means to exert old-fashioned ‘Cold War’ style political influence. The dark side of vaccine diplomacy.”

Moderately effective

Dr Anthony Fauci, Director of NIAID and White House coronavirus advisor had already said that chances of creating a highly effective vaccine that provides 98% or more protection are slim. Chances are that the first vaccine to become available will be only partially effective, if at all.

“We don’t know yet what the efficacy might be. We don’t know if it will be 50 or 60%. I’d like it to be 75% or more,” Dr Fauci said in a webinar hosted by Brown University.

Even the FDA has kept the threshold low for approving COVID-19 vaccines. The FDA has said it would authorise a coronavirus vaccine so long as it is safe and at least 50% effective, FDA commissioner Dr Stephen Hahn said in an interview with Dr Howard Bauchner of the Journal of the American Medical Association.

Partially effective vaccine and herd immunity

When a vaccine is only partially effective, greater percentage of people need to be immunised for achieving herd immunity. “Besides efficacy, effectiveness of the vaccine in protecting individuals may vary. If the vaccine is only about 50% efficacious and even if the effectiveness is 80%, then only about one-third or so will be protected even if vaccine coverage is 100%,” says Dr Babu.