Publication Of Sputnik V Results Shore Up Prospects Of “Elusive Trio” – But Answers Still Needed On China’s COVID-19 Vaccines Medical Innovation 04/02/2021 • Svĕt Lustig Vijay & Vijay Shankar Balakrishnan Share this:Click to share on Twitter (Opens in new window)Click to share on LinkedIn (Opens in new window)Click to share on Facebook (Opens in new window)Click to print (Opens in new window) Sputnik V is 91.6% effective in all age groups and 100% effective against moderate and severe disease News of the successful trial results of the Russian Sputnik vaccine, published on Wednesday by The Lancet has shored up the prospects of quick vaccine access for dozens of countries that have pinned their hopes on Russian or Chinese vaccine alternatives – as rich countries buy up the bulk of supplies of high-tech vaccines and new coronavirus variants supercharge transmission around the globe. But for now, at least, the Russian vaccine has pulled far ahead of the Chinese candidates – not only in terms of price – USD$ 10 per dose – but also reported efficacy and safety – in the wake of the published Phase 3 trial results for the Sputnik vaccine. The study, which was based on almost 22,000 participants, found that Sputnik was safe, and 91.6 % effective in preventing symptomatic COVID-19 cases, trailing behind Pfizer’s and Moderna’s vaccines by just a few percentage points. It was also effective in preventing severe COVID amongst clinical trial participants, which included a significant number of trial participants over the age of 60 and some even older than 80. The vaccine was developed by Russia’s Gamaleya National Research Institute of Epidemiology and Microbiology. The wave of interest comes at a time when large additional vaccine contributions by pharma companies based in rich countries to the international COVAX facility have failed to materialize. That has left many countries around the world scrambling on the open market for bilateral vaccine deals – sealed at uneven prices. Not incidentally, neither China nor Russia have so far offered any vaccines to the COVAX facility. Meanwhile, delivery timelines for AstraZeneca and Pfizer vaccines across high-income Europe have been delayed. Johnson and Johnson’s one-shot vaccine delivered lackluster results. And one of the world’s most storied vaccine-makers, Merck, recently reported that neither of its coronavirus vaccine candidates stimulates the immune system. Not only are countries seeking quick access and affordability, they are also seeking alternatives that can be distributed to energy-strapped health facilities without the need for ultra-cold freezers, which is a requirement for Moderna’s and Pfizer’s expensive mRNA vaccines. Russia’s Sputnik vaccine now seems to be checking all the right boxes. That makes it a significant alternative to the pricier and more temperature-sensitive mRNA vaccines by Moderna and Pfizer. If the clinical trial results published in The Lancet hold up to scrutiny, Sputnik’s results appear to be more robust, so far, than AstraZeneca’s already approved vaccine, not to mention the next Johnson & Johnson and Novavax vaccine candidates which are due to submit requests soon for US Food and Drug Administration (FDA) regulatory approval, and which are similarly affordable and easy to store – but with poorer efficacy results. President Putin announced Sputnik’s approval to Government members in August 2020 Many Factors Need to be Considered in Choosing a Vaccine “Many decisions need to be factored into selecting a vaccine as well as efficacy and safety,” Sheena Cruickshank, an immunologist at University of Manchester, told Health Policy Watch in an interview. “It’s important to think of the cost, storage, transport and feasibility of a vaccine too [so that] it can be readily administered in remote communities, without the need for refrigeration.” Jens Spahn, Germany’s health minister has said that he saw no fundamental obstacle to the use of Russian or Chinese vaccines, if the vaccines were to be approved by the European Medicines Agency (EMA). Sputnik has reportedly considered that – but not yet submitted a dossier. Spahn’s comment came against reports of worldwide distrust of Russian and Chinese vaccines, according to a recent poll by YouGov. As noted by Judy Twigg, global health expert with the Center for Strategic and International Studies, in a recent Op-Ed in the Moscow Times: “Sputnik V appears to be a sound vaccine, but Russia damaged its scientific credibility with premature and exaggerated claims of success.” My op-ed in today’s @MoscowTimes, arguing that Russia’s harmed its own scientific credibility with rushed approval and exaggerated claims for Sputnik V — even though the vaccine appears to be reasonably safe and effective. https://t.co/HbgOQFB5Y9 — Judy Twigg (@jtwigg9) January 22, 2021 “Regardless of the country in which a vaccine is manufactured, if they are safe and effective, they can help cope with the pandemic,” Spahn told the Frankfurter Allgemeine Zeitung newspaper Sunday, adding that any vaccine would have to be approved by the EMA before being rolled out in the bloc. Russia Squarely in the Competitive Ring – While China Muddying Waters With Propaganda Campaign Researcher prepares Sputnik V vaccine While Russia’s often boastful marketing campaign, with the RDIF CEO referring to it as “the best vaccine in the world,” raised bristles – the decision to take the route of a peer reviewed publication means that the Sputnik vaccine has now placed itself squarely in the competitive ring of western countries. In contrast, results of the Chinese Sinopharm vaccine’s multi-country trials, reportedly yielding results of 79.3% – 86% efficacy, remain unpublished. A second Chinese vaccine, by Sinovac, also has failed to publish peer reviewed results. Company announcements of Phase 3 results in four different countries have also yielded wildly varied efficacy scores ranging from 50.3% – 91.3%. The poor showing of Sinovac’s vaccine in Brazil was particularly disappointing; researchers at Brazil’s independent Butantan biomedical centre said the vaccine displayed a mediocre 50% efficacy result in the second interim analysis of a late-stage clinical trial in Brazil. China also has muddied the waters by launching its own propaganda campaign attacking the products of its western competitors. It has claimed that the shots by Pfizer and Moderna are ineffective, risky or even deadly. While the campaign by so-called “wolf warrior” diplomats was intended to reinforce the image of the Chinese home-brews, it may also undermine confidence in the Chinese vaccines – even if they do ultimately show robust results. However, even if Chinese vaccines perform less well than others, if they can at least meet the WHO and US FDA baseline of 50% efficacy, they might still be a “really great thing to have” in regions that are “absolutely desperate,” says Hilda Bastian, a public health researcher at Australia’s Bond University. “When you’ve got communities that are absolutely desperate, and have no other choice, then this is a really great thing to have,” she told Nature, referring to China’s Sinovac candidate. News on the Chinese vaccines is not all bad either. A recent preprint paper, which has not undergone peer review, suggests that Sinopharm’s vaccine held up well against a South African SARS-CoV2 variant (501Y.V2). In the analysis of blood samples from a dozen vaccinated participants, the vaccine’s neutralizing power was only reduced by a factor of 1.6 when it was exposed to the variant. In comparison, a similar study by Moderna of blood samples tested against the same variant reported a sixfold reduction – although Moderna scientists have said that the vaccine is still effective: “Despite this reduction, neutralizing titer levels with B.1.351 remain above levels that are expected to be protective,” Moderna’s Chief Scientist Tal Zaks told a recent investors’ session. First shipment of Sinopharm vaccine reached Peru for clinical trials in September last year More Than 50 Nations Have Eyed Russian Vaccine & 24 Have Requested Two Chinese Vaccines According to the Russian Direct Investment Fund (RDIF), which is marketing the Sputnik vaccine abroad, some fifty countries have already requested over 1.2 billion doses of the Sputnik vaccine. Meanwhile, at least 24 countries have sealed deals with Sinovac and Sinopharm’s leading vaccine candidate, BBIBP-CorV, co-developed with the Beijing Institute of Biological Products. Like Sputnik, both can be stored in a conventional refrigerator. Together, Sinopharm and Sinovac aim to produce two billion doses this year, which is on par with the total number of doses that the international COVAX facility hopes to supply to countries in need this year – although neither company has offered COVAX any vaccine supplies. Summary of features of Sputnik, Sinovac and Sinopharm vaccine. (HPW/Svet Lustig) Sputnik’s Technology Delivers A Double Whammy Sinovac’s vaccine reaches Brazil’s Sao Paolo airport Sputnik’s vaccine technology relies on a chemically crippled common cold virus to deliver double-stranded DNA that codes for the SARS-CoV2 spike protein, sparking an immune reaction. According to RDIF’s CEO, this platform represents a safe bet compared to novel delivery strategies that have never been tested in humans, like AstraZeneca’s use of a monkey adenovirus or even Pfizer’s and Moderna’s mRNA technologies. Another feature that sets Sputnik apart from other adenoviral vaccines is its delivery strategy. Instead of delivering the same virus in both shots, Sputnik consists of two distinct adenoviruses to prime and then boost the immune response. “Its clever design bases its two doses on different viral vectors, in principle producing a strong, long-term immune response,” noted Twigg in her recent op-ed. Its’ advocates claim this might help it achieve longer-lasting protection against the coronavirus – but this has yet to be demonstrated, particularly for older people and those with chronic diseases – “seems promising, however, we await to see what happens in people over 60 with underlying conditions,” observed Tracy Hussell, a University of Manchester immunologist. At the same time, AstraZeneca hopes to take advantage of this method to bolster its own vaccine with a “booster” shot of Sputnik. Important Data Still Missing For Sputnik Russian military personnel receives Sputnik V vaccine Despite the recent fanfare around the Lancet publication of Sputnik results, important data is still missing from the Sputnik file. Preclinical data, including from animal trials, remains unpublished and some of those trials may be methodologically flawed, Cruickshank from the University of Manchester has said. In these studies, Sputnik reportedly conferred a protection of “100%” after hamsters and marmosets were injected with a large quantity of SARS-CoV-2 virus. And although other Phase I/II trial data was also published in The Lancet, it was met with rebuke for its open-label methodology, failure to randomize patients, and exclusion of women and older people – all of which may have overestimated Sputnik’s performance, noted Cruickshank. While the chief author of The Lancet piece, Gamaleya’s Denis Logunov, has acknowledged these shortcomings, in an interview with Health Policy Watch, he stressed that ongoing Phase III trials that are larger and more robust should help answer these questions. Apart from the late-stage trial in Russia, others are underway in over 40,000 participants in the UAE, Egypt, Venezuela, Belarus and India. Prices Also Make Sputnik and AstraZeneca Most Accessible For Now Vaccine prices per dose based on developer, compiled from various sources. (HPW/Svet Lustig) What is clear for now is that AstraZeneca and Sputnik vaccines seem to be the most accessible to low- and middle-income countries. At USD$3 per dose, AstraZeneca’s vaccine produced by India’s Serum Institute, is still three times cheaper than Sputnik, which is priced at USD$10 per dose. Nonetheless, Sputnik’s has become more competitive after Uganda agreed to pay USD$7 per dose – USD$14 for two doses of the AstraZeneca vaccine, plus another USD$3 for shipping. In comparison, prices of Chinese vaccines are extremely high – at least officially. Sinovac’s vaccine is officially priced at USD$30 per dose and Sinopharm’s vaccine at USD$70 per dose. That makes Sinopharm’s vaccine more than twice as expensive as those from Pfizer and Moderna, eight times more than Sputnik – and twenty times more than AstraZeneca. Thus, unless Chinese vaccine-makers reduce their prices for low- and middle-income countries, they may fail to make a dent into existing vaccine vacuums. Sputnik: Distribution Plans See Expansion Beyond Russia Kirill Dmitriev, head of the RDIF So far, Russia has used its supply of Sputnik to vaccinate over a million Russians, less than 1% of its population of 144 million. Meanwhile, Argentina has already vaccinated 300,000 people. As a next stage, the RDIF plans to begin exporting the vaccine, Dmitriev told Health Policy Watch in a November interview. Local production of the vaccine has already begun in India, South Korea, Brazil, China, and is set to begin in Kazakhstan and Belarus – although Turkey and Iran are also expected to produce the vaccine, said Dmitriev on Tuesday. “Our strategy right now is that most of the vaccines produced in Russia will be used for the Russian market…hopefully within a year, we could start exporting our vaccine also to the rest of the world…to satisfy the demand across the globe,” he said last year. So far, the vaccine has been approved by 18 regulatory agencies across the world, including: Turkmenistan, Belarus, Serbia, Hungary, Nicaragua, Mexico, Venezuela, Bolivia, Argentina, Paraguay, Palestine, UAE, Iran, Republic of Guinea, Tunisia, Algeria and Armenia. In the wake of The Lancet publication, up to 26 countries are expected to approve the vaccine, said Dmietriev at the press conference on Tuesday. Countries that have struck firm deals with RDIF include: Country Deal Source Argentina Has bought 10 million doses. Reuters Bolivia Has bought 5.2 million doses. RDIF Brazil Plans to produce 150 million doses in 2021. RDIF Guinea Has bought 2 million doses Africa News India Plans to manufacture 100 million doses a year. Reuters Kazakhstan Plans for domestic production of 2 million doses in 2021 RDIF Mexico Has bought 24 million doses. Reuters Israel, a high-income country that has already vaccinated a fifth of its population and almost three quarters of people over 70, has also eyed Sputnik. Zeev Rotstein, the head of Israel’s Hadassah Medical Center, has asked the Ministry of Health to purchase one million vaccine doses. “The diversification of vaccine sources is the kind of policy that we feel is important,” Rotstein said in an interview with Health Policy Watch in mid-November. Although Israel has since rolled out its campaign almost exclusively around the Pfizer vaccine – Rotstein has continued to tell the media that the Sputnik vaccine can remain a useful alternative – either domestically or for use in the hospital’s Russian medical center affiliate. Right next door, the Palestinian Authority has approved the Sputnik vaccine and is expecting delivery of the first 50,000 doses this month, followed by AstraZeneca vaccines in mid-March. It has also received 5,000 Pfizer vaccines from Israel immediately for front-line health workers. There had, however, been some hesitancy around the use of the Sputnik vaccine – which the peer reviewed results may now help to dissipate. Sinovac – Struck Deals for over 380 Million Doses – Even Though Most Recent Trials Had Poor Showings Healthcare worker in Chile opens up Sinovac vaccine Among all of the vaccines under development, including Sputnik, the technology being used in the Chinese vaccines is also the oldest. It is based on a century-old practice in which an “inactivated” strain of the SARS-CoV-2 that cannot replicate in human cells is injected into the body, says the WHO. Even so, the research institutions backing the vaccines are not unknown to the west. One of the two Chinese vaccines is being developed by Sinovac, a firm that has successfully marketed a WHO-approved hepatitis vaccine. In late December, Sinovac proudly announced an efficacy of 91.3% in a Turkish trial, but since then, the vaccine’s performance has consistently gone downhill. Subsequent trials yielded 78% in Brazil, 65.3% in Indonesia – and most disappointingly – 50.3% in a second Brazilian trial. If Sinovac’s vaccine efficacy dips below 50%, it would fail to hold up to the WHO’s and FDA’s minimum efficacy threshold. And it could become even less useful against novel coronavirus variants that are already undermining the best vaccines that currently available – as per indicative results from studies and trials by Moderna, Pfizer and Novavax. Some experts, however, have floated the idea that Brazil’s second interim analysis included more people with milder infections than in the first, thus reducing its efficacy. They also noted that Brazil’s trial of 12,000 people – the largest so far – exclusively recruited healthcare workers that are more likely to report mild infections, in comparison to other trials that recruited members of the general public, like those in Turkey or Indonesia. In her interview with Health Policy Watch, Cruickshank observed that background infection rates in the country is another factor: “It’s important to consider how common the disease is in the area where trials are carried out…If there is little virus in an area then fewer people may contract disease to assess how well a vaccine works.” The Sinovac analyses also varied in terms of the time interval between the administration of the first and second vaccine doses – which may have also affected efficacy, said a spokesman from Sinovac. And a small sub-group of the last Brazilian trial, which received their vaccine doses 3 weeks apart, showed a higher efficacy (70%) than the larger group in which the vaccine was 50% efficacious – after receiving shots 2 weeks apart. In total, about 30,000 participants are still taking part in late-stage trials in Chile, Brazil, Turkey, Indonesia and China. If results from those trials are analysed transparently – then some of the outstanding questions will be answered. Despite the mixed results, the Sinovac vaccine has been approved for emergency use in China, which has vaccinated 7 million citizens, as well as Turkey, where 1.3 million people have been vaccinated, Indonesia, where 15,000 people have been vaccinated, and Chile. And Sinovac has already struck deals for over 380 million doses with a dozen countries, including Indonesia, Brazil and Turkey, among other countries. The number of Sinovac doses ordered across the top 10 countries, compiled from various sources. (HPW/Svet Lustig) Sinopharm Sealed Deals With At Least Six Countries in Latin America, Middle East & Europe In June last year, Governor of São Paulo João Doria announced a partnership between Sinovac and it’s Butantan Institute Despite its price, Sinopharm has already sealed deals with Argentina, Jordan, Morocco, Hungary, Serbia and Pakistan – which first bought 1.2 million doses outright and later received half a million additional doses as a “gift” from China. In terms of approval, China already approved Sinopharm’s vaccine for the general public late last year, and plans to extend it to minors by March. Outside China, countries that have already approved it include Argentina, Peru, Bahrain, Egypt, Hungary, Iraq, Jordan, Pakistan, Peru Republic of Serbia, Seychelles, and the United Arab Emirates, according to McGill’s COVID-19 Vaccine Tracker. And recently, the UAE extended the vaccine’s use to people aged 60 and above. With respect to vaccinations, one million Chinese citizens have already been inoculated with Sinopharm’s vaccine; outside China, inoculations have begun in the UAE, and further vaccination campaigns are set to begin in Egypt as well as Serbia, which became the first European country to receive doses of a Chinese vaccine last week. Sinopharm – Efficacy, Safety & Clinical Trials In a similar vein, Sinopharm’s vaccine has also puzzled scientists, with an efficacy of 79.3% in China and 86% in the UAE. Like Sinovac, Sinopharm has tried to reassure the world that both efficacy results are “real” and “valid,” explaining that countries have distinct case definitions for COVID-19, thus affecting national estimates of efficacy. “Because the standards of diagnosis of infection cases and the review process of Phase III clinical trial vary in different countries, the 86% efficacy rate announced by UAE and 79.34% by China are both real and valid,” the firm said in a press release. In total, some 66,000 volunteers from 125 nations are taking part in the company’s late stage clinical trials, including Argentina, Peru, Bahrain, Egypt, Jordan and the United Arab Emirates, according to McGill’s vaccine tracker. WHO Prequalification For Chinese & Russian Vaccines Another Route Of Approval In light of the results reported in The Lancet, the next question is whether the Sputnik vaccine might be submitted to the European Medicines Agency (EMA) for regulatory approval. Meanwhile, however, Gamaleya has submitted a dossier to WHO for “prequalification” of the Sputnik vaccine on WHO’s “Emergency Use Listing” – an avenue that offers another acceptable route to approval by a global health authority. Sinopharm and Sinovac also have submitted files to WHO, and these are currently under review as well, WHO officials said in late January. “We have full dossiers from three other drug companies right now, Sinopharm, Sinovac, and the Serum Institute of India and they are under assessment,” said WHO’s Dr Mariangela Simao, Assistant Director-General for Access to Medicines, who said the real time status of WHO review and approval for all vaccines can be tracked on the WHO’s website. “We have a mission in China right now, to do the inspections in Sinopharm, in Sinovac,” she added. Still, for now, “nothing” can be said about the potential of these vaccines before vaccine makers reveal the datasets, warned Jarbas Barbosa in January, who is the assistant director of the WHO’s Regional Office of the Americas/Pan American Health Organization (PAHO), noting that neither the Russian nor the Chinese vaccine-makers have publicly released late stage clinical trial results – although they recently submitted their vaccine dossiers to WHO for review. “We only can say something about these vaccines when we reveal this data, before that we cannot say nothing based on press releases from the producers,” PAHO’s Jarbas Barbosa told Health Policy Watch at a press conference in January. If WHO Pre-Approves Sputnik, Sinopharm & Sinovac – Will they Really Donate To COVAX? WHO Director-General, Dr Tedros Adhanom Ghebreyesus WHO’s director-general Dr Tedros Adhanom Ghrebreyesus also recently warned member states against the purchase of vaccines that have not been approved by a strict regulatory authority. “We call on all countries introducing vaccines to only use vaccines that meet rigorous international standards for safety, efficacy and quality, and to accelerate readiness for deployment,” said Tedros, where he also called out rich countries for hoarding doses and vaccine producers for failing to provide WHO with timely data on vaccine efficacy. The WHO’s “prequalification” of a vaccine would also clear the way for the global COVAX facility, co-sponsored by WHO, to buy the vaccines in bulk. The COVAX initiative, also co-sponsored by UNICEF and Gavi, The Vaccine Alliance, aims to distribute 2.3 billion vaccines following a new contribution from Pfizer. “What’s important to understand is that pre-qualification is done, so that the international organizations such as UNICEF and others are comfortable with vaccines and able to purchase them,” David Heymann, former WHO assistant director for Health Security and professor at the London School of Hygiene & Tropical Medicine, told Health Policy Watch. “So if a vaccine doesn’t have a pre-qualification from WHO, it won’t be bought by organizations like GAVI or UNICEF.” The initiative, designed to bolster equitable access to vaccines, is one that both Russia and China profess to support. In a global market where vaccine nationalism is running rampant – it remains to be seen if, in the event that Russia’s Sputnik, and China’s Sinopharm and Sinovac are greenlit by COVAX – whether they will follow the example of AstraZeneca and Pfizer – and offer their vaccines to the global market in bulk and at cost. –Vijay Shankar contributed significant reporting on Sputnik. Image Credits: RDIF, Kremlin, Peruvian Ministry of External Affairs, São Paulo State Government, Ministry of Defence of the Russian Federation, World Economic Forum, Pontificia Universidad Católica de Chile, State of Sao Paolo, WHO / Christopher Black . Share this:Click to share on Twitter (Opens in new window)Click to share on LinkedIn (Opens in new window)Click to share on Facebook (Opens in new window)Click to print (Opens in new window) Combat the infodemic in health information and support health policy reporting from the global South. 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