Virus World

SARS-CoV-2 has caused a global pandemic that has infected more than 250 million people worldwide. Although several vaccine candidates have received emergency use authorization, there is still limited knowledge on how vaccine dosing affects immune responses. We performed mechanistic studies in mice to understand how the priming dose of an adenovirus-based SARS-CoV-2 vaccine affects long-term immunity to SARS-CoV-2. We first primed C57BL/6 mice with an adenovirus serotype 5 vaccine encoding the SARS-CoV-2 spike protein, similar to that used in the CanSino and Sputnik V vaccines. The vaccine prime was administered at either a standard dose or 1000-fold lower dose, followed by a boost with the standard dose 4 weeks later. Initially, the low dose prime induced lower immune responses relative to the standard dose prime. However, the low dose prime elicited immune responses that were qualitatively superior and, upon boosting, exhibited substantially more potent recall and functional capacity. We also report similar effects with a simian immunodeficiency virus (SIV) vaccine. These findings show an unexpected advantage of fractionating vaccine prime doses, warranting a reevaluation of vaccine trial protocols for SARS-CoV-2 and other pathogens.

Published in Science Immunology:

https://doi.org/10.1126/sciimmunol.abi8635

BUENOS AIRES — President Alberto Fernández of Argentina tested positive for Covid-19 on Saturday and was experiencing mild symptoms despite having been vaccinated earlier this year, becoming the latest in a series of world leaders who have contracted the virus. In a series of tweets sent early Saturday, Mr. Fernández said a “light headache” and a temperature of 99.1 degrees had prompted him to take a quick antigen test. Its positive finding was confirmed later Saturday by a more rigorous P.C.R. test, said Dr. Federico Saavedra, the president’s physician. Mr. Fernández’s symptoms were “mild due in large part to the protective effect of the vaccine,” Dr. Saavedra said. The president, who first learned the preliminary result on Friday, his 62nd birthday, said he would remain in isolation. “I am physically well, and although I would have liked to end my birthday without this news, I’m also in good spirits,” the president wrote on Twitter. Mr. Fernández joins a list of world leaders who have contracted the virus, including Andrés Manuel López Obrador of Mexico, Jair Bolsonaro of Brazil, Emmanuel Macron of France and Donald Trump of the United States, during the final months of his presidency. But Mr. Fernández appears to be the first of those leaders to test positive for Covid-19 after having been fully vaccinated. He received the first dose of Russia’s Sputnik V vaccine on Jan. 21 and the second dose on Feb. 11.

Russia's Sputnik V vaccine is 92% effective at protecting people from COVID-19 according to interim trial results, the country's sovereign wealth fund said on Wednesday, as Moscow rushes to keep pace with Western drugmakers in the race for a shot. Russia's results are only the second from a late-stage human trial, following on swiftly from data released on Monday by Pfizer Inc PFE.N and BioNTech BNTX.O, which said their shot was also more than 90% effective. While experts said the Russian data was encouraging and reinforced the idea the pandemic could be halted by vaccines, they warned that the results were only based on a small number of trial volunteers who had contracted COVID-19. The analysis was conducted after 20 participants developed the virus and examined how many had received the vaccine versus a placebo. That is significantly lower than the 94 infections in the trial of the vaccine being developed by Pfizer and BioNTech.

“I assume there was political pressure after the press release from Pfizer and BioNTech earlier in the week to now draw level with their own data,” said Bodo Plachter, deputy director of the Institute of Virology at the Mainz University. “What is missing for now is an analysis of statistical significance.” To confirm the efficacy rate of its vaccine, Pfizer said it would continue its trial until there were 164 COVID-19 cases. The Russian Direct Investment Fund (RDIF), which has been backing Sputnik V’s development, said the Russian trial would continue for six months. Alexander Gintsburg, director of the Gamaleya Institute which developed the vaccine, said the interim results demonstrated that Sputnik V was effective and mass vaccinations would be rolled out in Russia in the coming weeks. In later comments, aired by Rossiya-24 state TV channel, he said at least 1.5 million people in Russia were expected to receive the shot by the end of the year. He added that around 40,000 to 45,000 Russians had already been vaccinated. European stocks and U.S. stock futures extended their gains slightly after Russia’s announcement though the reaction was far more muted than after Pfizer’s results. China’s Sinopharm, which is running large-scale late-stage clinical trials for two COVID-19 vaccine candidates, said on Wednesday that its data was better than expected, though it did not give further details. 

‘NOT A COMPETITION’

Successful vaccines are seen as a crucial to restoring daily life around the world by helping end the pandemic that has killed more than 1.26 million people, shuttered businesses and put millions out of work. However, experts said knowledge about the Russian trial’s design was sparse, making it hard to interpret the data. Scientists have raised concerns about the speed at which Moscow has worked, giving the regulatory go-ahead for the shot and launching mass vaccinations before full trials to test its safety and efficacy had been completed. “This is not a competition. We need all trials to be carried out to the highest possible standards and it is particularly important that the pre-set criteria for unblinding the trial data are adhered to avoid cherry picking the data,” said Eleanor Riley, a professor of immunology and infectious disease at the University of Edinburgh.

On Tuesday, Russian President Vladimir Putin announced that his country had registered the world's first coronavirus vaccine, named ‘Sputnik V’. The president said that one of his daughters had tested the vaccine on herself.

What we know about the vaccine:

• Developed by Moscow’s Gamaleya Research Institute of Epidemiology and Microbiology, the dose is based on a platform already used for six other vaccines, according to Russian Minister of Health Mikhail Murashko.
• The Ministry of Health registered ‘Sputnik V’ as a solution to be injected.
• According to the results of clinical studies, the vaccine has shown both high efficacy and safety.
• All the volunteers developed high titers [concentration levels] of antibodies to Covid-19, Murashko noted.
• He also said that “none of them had serious complications” after receiving the vaccine.
• After vaccination, immunity to Covid-19 can last up to two years, the Health Ministry claimed. 

How the vaccine will be distributed:

• President Putin expects that mass production of the coronavirus vaccine will begin in the near future.
• The solution will be produced at two sites: The Russian Ministry of Health’s Gamaleya  Institute and the domestic biopharmaceutical company Binnopharm.
• Some foreign countries have already shown interest in acquiring doses of the Russian vaccine.

Vaccination:

• Medical workers and teachers will be the first to receive the vaccine. 
• Vaccination of medical professionals could begin in late August or September.
• ‘Sputnik V’ will be available to the general public on January 1, 2021.
• Vaccination will be voluntary in Russia.

The Russian Direct Investment Fund and the Gamaleya  Institute of Epidemiology and Microbiology have launched a new website with information about ‘Sputnik V’. 

Agency declines import permit, claiming crippled adenovirus that serves as vaccine is active in second doses.  A confusing and unusually nasty fight broke out this week over the safety of a Russian COVID-19 vaccine known as Sputnik V after a Brazilian health agency declined on Monday to authorize its import because of quality and safety concerns. The stakes escalated yesterday when the Twitter account officially associated with the vaccine said “Sputnik V is undertaking a legal defamation proceeding” against Brazil’s regulators. In an online press conference several hours later, the Brazilian Health Regulatory Agency (Anvisa) defended its decision, maintaining that documentation from some of the Russian facilities making Sputnik V shows that one of its two doses contains adenoviruses capable of replication, a potential danger to vaccine recipients. The vaccine uses two different adenoviruses, which cause the common cold, to deliver the gene for the spike protein of SARS-CoV-2, the virus that causes COVD-19. Both are supposed to be stripped of a key gene that allows them to replicate.

The Monday announcement left many scientists and media outlets believing Anvisa had directly tested Sputnik V for replicating adenoviruses, which would be unusual for a regulatory agency. But Anvisa has since clarified—it had not and was relying on information provided by the Gamaleya National Center of Epidemiology and Microbiology, the Moscow-based developer of the vaccine. “The data we evaluated shows the presence of replicating virus,” Gustavo Mendes, general manager of medicines and biological products at Anvisa, said at the press conference. Anvisa would not accept the vaccine, he said, without further studies to indicate it is safe. Gamaleya said in a statement on its website that Anvisa’s allegations “have no scientific grounds and cannot be treated seriously.” The research institute added that “no replication-competent adenoviruses (RCA) were ever found in any of the Sputnik V vaccine batches” and said a four-stage purification process prevents contamination. The furor comes as Brazil, which has one of the highest burdens of COVID-19 in the world, is desperately trying to expand its vaccination campaign. The country has vaccinated just 14% of its people with a first dose and governors from some states hoped to bolster that effort by grouping together to buy 30 million doses of Sputnik V.

The spat has bewildered and divided outsider observers, in Brazil and elsewhere. Some scientists have used social media to decry the apparent contamination and some have denounced the aggressive response by Sputnik V’s backers, who were already under fire for releasing little data on the vaccine’s safety record. On Wednesday, an agency of the European Union also issued a report criticizing Russia’s promotional effort for Sputnik V for providing disinformation. Other scientists, however, have questioned whether Anvisa appropriately interpreted the information provided by Sputnik V’s makers, and whether the media has too readily accepted the agency’s claim that the vaccine is contaminated. The stakes are high because Sputnik V has been authorized for use in more than 60 countries, although neither the World Health Organization nor the European Medicines Agency has yet authorized it. “We need this vaccine. It’s cheap. It’s effective. It’s easy to store and transport,” says Hildegund Ertl, an adenovirus vaccine scientist at the Wistar Institute. “If the press could just take a deep breath before they rush to conclusions it would really help us all.” One of the scientists who criticized Sputnik V this week on Twitter said she is keeping an open mind. “I will be glad to correct myself in public should the data be shared,” says Angela Rasmussen, a virologist at the Vaccine and Infectious Disease Organization at the University of Saskatchewan. (Her Twitter thread about Anvisa’s decision got a response from Sputnik V’s account that read “please do not spread fake news.”)

Viruses reborn?

The Anvisa review of Sputnik V was triggered because the Brazilian governors needed the agency’s sign-off to import the vaccine. Although complaints about Russia’s lack of transparency with Sputnik V data have simmered for months, many public health officials and scientists worldwide had been reassured when The Lancet recently published results from nearly 20,000 people in a clinical trial. The study showed the vaccine was safe and had an efficacy of 91.6% at preventing symptomatic COVID-19. Both of the adenoviruses that make up Sputnik V, known as Ad5 and Ad26, are churned out by cultured human cells called HEK293 cells. The adenoviruses ferry the coronavirus spike gene to the vaccine recipient’s cells, which then make spike, prompting an immune response. In order to stop the adenoviruses from replicating once inside their human host, the vaccinemaker removed a gene they need for reproduction, called E1. The viruses can copy themselves in HEK293 cells, which are engineered to have a stand-in E1 gene, but they are not supposed to be able to replicate once they are separated from the human cells and packaged in the final vaccine product. It’s long been known that Ad5 can on rare occasions acquire the E1 gene from the HEK293 cells, converting what is supposed to be a crippled virus into an RCA. Although adenoviruses typically cause mild colds, they can rarely kill people, and immunocompromised people who receive a vaccine that inadvertently contains RCAs could be at particular risk. Vaccine makers and others have developed tests to check for replicating adenoviruses in their products. Anvisa said that although the standard worldwide has been zero tolerance for the presence of replicating adenovirus in the vaccine, Gamaleya established an acceptable limit of 5000 replication-capable virus particles per vaccine dose. The Russian quality control documents displayed by Anvisa during the press conference state the batches tested had “less than 100” replication-capable particles per dose. During yesterday’s press conference, Mendes also showed video of parts of an online meeting in March between officials from Anvisa and the vaccine’s developer. In one of the clips, Anvisa officials ask Gamaleya representatives why they had not changed their production methods once they “had detected the RCA occurrence in your production” The Gamaleya representatives responded that they were aware of the risk, but that changing the process “would take too much time.” Mendes noted that Anvisa has analyzed the quality control documentation on other adenovirus-based COVID-19 vaccines, such as those made by AstraZeneca and Johnson & Johnson, and found no evidence of replication-competent viruses in those companies’ final products.....

Published in Science (April 30, 2021):

https://doi.org/10.1126/science.abj2483

A peer-reviewed article in The Lancet shows the vaccine has an impressive 91.6 percent efficacy rate against the virus and is completely protective against severe cases of Covid-19.  MOSCOW — Russia cleared a hurdle in its vaccine rollout on Monday with the publication in the respected British medical journal The Lancet of late-stage trial results showing that the country’s Sputnik V vaccine is safe and highly effective. The publication is sure to buoy the Russian government’s promotion of the vaccine at home and around the world, strengthening the Kremlin’s hand in vaccine diplomacy with a credible endorsement of the product’s safety. Russia drew criticism from Western experts when it approved the vaccine for emergency use in August — before late-stage trials had even begun — and started vaccinations that month. Moscow claimed victory in the vaccine race, as it had decades earlier in the space race with the launch of the Sputnik satellite, though at the time other vaccines were further along in testing. In the end, its politicized rollout only served to deepen skepticism.

Despite Putin’s reported endorsement, little-tested vaccine is not approved for widespread use until 2021. In a startling and confusing move, Russia claimed today it had approved the world’s first COVID-19 vaccine, as the nation’s Ministry of Health issued what’s called a registration certificate for a vaccine candidate that has been tested in just 76 people. The certificate allows the vaccine, developed by the Gamaleya Research Institute of Epidemiology and Microbiology in Moscow, to be given to “a small number of citizens from vulnerable groups,” including medical staff and the elderly, a Ministry of Health spokesperson tells ScienceInsider. But the certificate stipulates that the vaccine cannot be used widely until 1 January 2021, presumably after larger clinical trials have been completed. Scientists around the world immediately denounced the certification as premature and inappropriate, as the Gamaleya vaccine has yet to complete a trial that convincingly shows it is safe and effective in a large group of people. Even some within Russia challenged the move. “It's ridiculous,” says Svetlana Zavidova, a lawyer who heads the Association of Clinical Research Organizations in Russia. “I feel only shame for our country.” Zavidova, who has worked on clinical trials for 20 years and anticipated the approval, yesterday sent an appeal to the Ministry of Health to postpone registering the vaccine until proper efficacy trials are completed. “Accelerated registration will no longer make Russia a leader in this race, it will only expose end users of the vaccine, citizens of the country of the Russian Federation, to unnecessary danger,” she wrote on behalf of the clinical research group.

Gamaleya has developed vaccines before, and Mikhail Murashko, the Russian minister of health, said in a government press release that the COVID-19 vaccine showed “high efficacy and safety” and there were no serious side effects. The same release suggested the vaccine would confer 2 years of immunity to SARS-CoV-2, the virus that causes COVID-19. That estimate is apparently based on vaccines Gamaleya has made with similar technology.  Russian President Vladimir Putin reportedly endorsed the use of the vaccine, which is dubbed “Sputnik V,” saying it had “passed all necessary steps” and noting that one of his adult daughters had received it. (Putin has not clearly acknowledged his children in public, but he does sometimes refer to them; one is a medical doctor in Moscow.) Putin, who apparently made these comments at a government meeting, added, “I hope we can start a massive release of this vaccine soon.” 

The Russian registration certificate gives few details about the vaccine, which is being manufactured by Binnopharm in Zelenograd. The company says it can produce 1.5 million doses of the product per year and hopes to expand its manufacturing capacity. More information is available in descriptions of two small trials of the candidate vaccine that appear on ClinicalTrials.gov, a website run by the U.S. National Institutes of Health. The vaccine consists of two shots that use different versions of adenoviruses, some of which cause the common cold, that Gamaleya researchers have engineered to carry the gene for the surface protein, or spike, of SARS-CoV-2. Apparently, the studies are comparing a single shot of adenovirus 26 with the spike gene to a scheme, known as prime-boost, that also gives a second dose 21 days later of a vaccine that contains the spike gene in adenovirus 5.

Some vaccine experts have raised concerns about COVID-19 vaccines that use adenovirus 5 in this way. In 2007, researchers stopped an HIV vaccine trial that used adenovirus 5 to shuttle in the gene for the surface protein of that virus after they found that it increased the likelihood of its transmission. 

In 2017, Gamelaya received approval in Russia for a vaccine that also used the adenovirus 5 vector to deliver the surface protein gene from the virus that causes Ebola. Researchers there used a similar strategy for a vaccine for Middle East respiratory syndrome, a disease caused by a coronavirus like the one responsible for COVID-19. It is still under development and has entered early stage clinical trials.  In the United States, the Food and Drug Administration (FDA) can approve the use of medicines prior to the completion of efficacy trials through what’s known as an emergency use authorization, and there has been growing concern that President Donald Trump will push for this with a COVID-19 vaccine to help his re-election prospects in November. Zavidova says Russia’s certification process is similar to FDA’s emergency use. But FDA has an independent advisory committee, largely consisting of academics, that routinely reviews vaccine approval applications.