Virus World

A single-dose dengue vaccine produced by Butantan Institute in São Paulo state (Brazil) prevents development of the disease in 79.6% of those vaccinated, according to an article published in The New England Journal of Medicine . Called Butantan-DV, the vaccine contains attenuated versions of all four dengue virus serotypes. The results of the ongoing Phase 3 trial show that it is safe and effective for all age groups between 2 and 59, and for people with or without a prior history of infection by dengue virus. "Publication of the article in the world's leading medical journal attests to the rigor and quality of the work done by researchers at 16 Brazilian centers located in all five regions of the country, and coordinated by Butantan Institute," infectious disease specialist Esper Kallás, first author of the article, told Agência FAPESP. "In June, we'll complete the five-year follow-up period. Once the data has been consolidated, we'll know how long the protection induced by the vaccine will last." Also according to Kallás, who heads Butantan Institute, the researchers plan to submit a report to ANVISA, Brazil's health surveillance agency, in the second half of this year in order to apply for registration of the vaccine.

"If all goes well, we'll win definitive approval for the vaccine in 2025. We already have the infrastructure to produce it at Butantan Institute, although it can still be perfected. After all, it's tetravalent, corresponding to four vaccines in one," he said. The article published today describes the results of the first two years of the Phase 3 clinical trial, which began in February 2016 and involves 16,235 participants in 13 states. Preliminary data disclosed by Butantan Institute in December 2022 pointed to overall efficacy of 79.6%. The results for each subgroup evaluated have now been detailed. Vaccine efficacy was 80.1% for participants aged 2-6, 77.8% for those aged 7-17, and 90.0% for 18-59 age group. Stratification by serological status showed protection for 73.6% of participants with no evidence of prior infection by dengue virus and 89.2% of those previously exposed to the virus. Efficacy was 89.5% against dengue serotype 1 (DENV-1) and 69.6% against serotype 2 (DENV-2). It was not possible to assess the vaccine's efficacy against serotypes 3 and 4 because they were not circulating during the follow-up period. Most adverse side effects were classified as mild or moderate. The main reactions were pain and redness at the injection site, headache, and fatigue. Severe adverse events relating to the vaccine were recorded for under 0.1% of all those vaccinated, and all of them recovered. "Findings from Phase 2 [the previous clinical trial] showed that the four attenuated viral serotypes in Butantan-DV multiply in the human organism and induce a balanced response in terms of antibody production. This leads us to conclude that its efficacy against DENV-3 and DENV-4 will also be good," said virologist Maurício Lacerda Nogueira, one of the coordinators of the trials.

Publication cired in N.E.J.M. (Feb. 1, 2024):

https://doi.org/10.1056/NEJMoa2301790 

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

Preliminary data from a study conducted at the University of Oxford indicates that the COVID-19 vaccine developed by AstraZeneca PLC is effective against the P1, or Brazilian, variant, a source with knowledge of the study told Reuters on Friday.  The data indicates that the vaccine will not need to be modified in order to protect against the variant, which is believed to have originated in the Amazonian city of Manaus, said the source, who requested anonymity as the results have not yet been made public. The source did not provide the exact efficacy of the vaccine against the variant. They said the full results of the study should be released soon, possibly in March.  Early results indicated the AstraZeneca vaccine was significantly less effective against the South African variant, which is similar to P1. South Africa subsequently paused the use of the vaccine in the country. The information comes as a plasma study published ahead of peer review on Monday (bit.ly/3bX3LBa) suggested the CoronaVac COVID-19 vaccine developed by China's Sinovac Biotech may not work effectively against the Brazilian variant. Responding to a request for comment, Fiocruz, which sent the samples that formed the basis of the AstraZeneca vaccine study, told Reuters it did not have any information on the study, as it was being led by AstraZeneca and the University of Oxford.  Representatives for AstraZeneca and the University of Oxford did not immediately respond to requests for comment. Brazil is currently confronting a brutal and long-lasting second wave of the coronavirus, hitting a daily record of 1,910 deaths on Wednesday. The P1 variant (also known as 20J/501Y.V3) is among the factors that epidemiologists believe is contributing to a rise in cases and deaths, and there has been concern in the scientific community about the variant’s resistance to vaccines.

A leading Chinese Covid-19 vaccine developed by Sinovac Biotech was just 50.38% effective in late-stage trials in Brazil, significantly lower than earlier results showed, according to a statement published by the government of Sao Paulo Tuesday.  While the number exceeds the threshold required for regulatory approval, it falls far below the 78% previously announced, raising questions as to the veracity of the data and fueling skepticism over the apparent lack of transparency regarding Chinese vaccines. Analysts said the efficacy rate of Sinovac's Coronavac vaccine in Brazil -- the lowest among its global competitors -- could affect international confidence in Chinese-made vaccines and hamper Beijing's effort to repair its image from its early mishandling of the initial outbreak by providing Covid-19 vaccines to developing countries. "The Butantan Institute and the Government of Sao Paulo report that the coronavirus vaccine achieved a 50.38% overall efficacy rate in the clinical study conducted in Brazil, in addition to (an efficacy rate of) 78% for mild cases and 100% for moderate and severe cases of Covid-19. All rates are higher than the 50% level required by the WHO (World Health Organization)," the statement released Tuesday said. The razor-thin margin for regulatory approval is likely to lead to concern among scientists, given that last week the Butantan institute released partial "clinical efficacy" results celebrating 78% to 100% efficacy in preventing infections. The state body financed the phase 3 trials of the vaccine, which involved 13,000 health workers across eight Brazilian states. "Regarding the overall efficacy of the analysis, we met the requirements of the World Health Organization with 50.38%," Ricardo Palacios, medical director for clinical research at the Butantan biomedical center in Sao Paulo said Tuesday during a news conference. However, on Tuesday, high-ranking members of the Brazilian Health Ministry told CNN affiliate CNN Brasil that "the effectiveness is borderline," and that because "It is at the limit. We have to wait for ANVISA (Brazilian Health Regulatory Agency) to evaluate." A representative of Sinovac said the company is discussing the result but declined to give further comment. The final efficacy rate of the vaccine will be determined by China's drug regulator, the National Medical Production Administration, according to the representative. 

Moderna Inc (MRNA.O) said on Wednesday early human trial data shows that a third dose of either its current COVID-19 shot or an experimental new vaccine candidate increases immunity against variants of COVID-19 first found in Brazil and South Africa.  The booster shots, given to volunteers previously inoculated with Moderna's two-dose vaccine regimen, also boosted antibodies against the original version of COVID-19, Moderna said. The early data comes from a 40-person trial testing both Moderna's existing shot and a version developed to protect against the South African variant of COVID-19 called mRNA-1273.351. Moderna is also studying a shot that combines both the new and existing vaccine. The results show that while booster shots of either version of the vaccine increased antibodies against all of the variants of COVID-19 tested in the trial, the new booster had a bigger response against the South African variant than the original vaccine.

"We are encouraged by these new data, which reinforce our confidence that our booster strategy should be protective" against the newer variants of COVID-19, Stephane Bancel, Moderna's chief executive officer, said in a statement. Both booster shots were well tolerated, with side effects similar to what volunteers in previous studies experienced from the second dose of its vaccine, Moderna said. The new variants of COVID-19 first discovered in South Africa and Brazil are thought to be more resistant to existing vaccines. Both variants have been detected in the United States but comprise only a small fraction of U.S. cases so far, according to federal data last updated in April. Moderna’s study is looking at levels of antibodies in participants’ blood that combat COVID-19, an early indication that they will be protected against the virus. It first announced it was studying ways to protect against the variants of COVID-19 in February.  Moderna expects to share additional data soon on another potential booster shot that mixes its existing COVID-19 vaccine with the newly developed shot. The U.S. government scientists at the National Institute of Allergy and Infectious Diseases (NIAID) is conducting a separate early stage study of mRNA-1273.351, Moderna said.

Moderna's Press Release (May 5, 2021):

https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-positive-initial-booster-data-against-sars-cov 

The COVID-19 vaccine from Pfizer Inc and BioNTech SE was able to neutralize a new variant of the coronavirus spreading rapidly in Brazil, according to a laboratory study published in the New England Journal of Medicine on Monday. Blood taken from people who had been given the vaccine neutralized an engineered version of the virus that contained the same mutations carried on the spike portion of the highly contagious P.1 variant first identified in Brazil, the study conducted by scientists from the companies and the University of Texas Medical Branch found.  The scientists said the neutralizing ability was roughly equivalent the vaccine’s effect on a previous less contagious version of the virus from last year. The spike, used by the virus to enter human cells, is the primary target of many COVID-19 vaccines.

In previously published studies, Pfizer had found that its vaccine neutralized other more contagious variants first identified in the United Kingdom and South Africa, although the South African variant may reduce protective antibodies elicited by the vaccine. Pfizer has said it believes its current vaccine is highly likely to still protect against the South African variant. However, the drugmaker is planning to test a third booster dose of their vaccine as well as a version retooled specifically to combat the variant in order to better understand the immune response.

Original Study Published in N.Eng. J. Medicine (March 8, 2021):

https://doi.org/10.1056/NEJMc2102017

NEW YORK: Pfizer and BioNTech's COVID-19 vaccine appeared to only lose a small bit of effectiveness against an engineered virus with three key mutations from the new variant found in South Africa, according to a laboratory study conducted by the US drugmaker. The study by Pfizer and scientists from the University of Texas Medical Branch (UTMB), which has not yet been peer-reviewed, showed a less than two-fold reduction in antibody titer levels, indicating the vaccine would likely still be effective in neutralising a virus with the so-called E484K and N501Y mutations found in the South African variant. The study was conducted on blood taken from people who had been given the vaccine. Its findings are limited, because it does not look at the full set of mutations found in the new South African variant. The scientists are currently engineering a virus with the full set of mutations and expect to have results from that in about two weeks, according to Pei-Yong Shi, an author of the study and a professor at UTMB.

The results are more encouraging than another non-peer reviewed study from scientists at Columbia University earlier on Wednesday which used a slightly different method and showed antibodies generated by the shots were significantly less effective against the South Africa variant. One possible reason for the difference could be that the Pfizer findings are based on an engineered coronavirus, and the Columbia study used a pseudovirus based on the vesicular stomatitis virus, a different type of virus, UTMB's Shi said.  He said he believes that finding in pseudoviruses should be validated using the real virus. The study also showed even better results against several key mutations from the highly transmissible UK variant of the virus. Shi said they were also working on an engineered virus with the full set of mutations from that variant as well.

Research cited available in bioRxiv (Jan. 27, 2021):

https://doi.org/10.1101/2021.01.27.427998

By Tuvan Gumrukcu and Ali Kucukgocmen ANKARA (Reuters) -A COVID-19 vaccine developed by China's Sinovac Biotech is 91.25% effective, according to interim data from a late-stage trial in Turkey, a potentially much better result than reported from a separate trial of the vaccine in Brazil.  Researchers in Brazil, which is also running a final Phase III trial of the vaccine, said on Wednesday the shot was more than 50% effective, but withheld full results at the company's request, raising questions about transparency. Turkish researchers said on Thursday no major side-effects were seen during their trial, apart from one person who had an allergic reaction. Common adverse effects caused by the vaccine were fever, mild pain and slight fatigue, they said.  The Turkish trials began on Sept. 14 and have included more than 7,000 volunteers, the researchers said, adding the results announced on Thursday were based on data from 1,322 people. 

Sinovac is the first Chinese vaccine maker to release details from late-stage clinical trials, following positive results from rival products developed by Pfizer, Moderna and AstraZeneca last month. The Turkish researchers, speaking alongside Health Minister Fahrettin Koca, said 26 of the 29 people who were infected during the trial were given placebos, adding the trial would continue until 40 people become infected. "We are now certain that the vaccine is effective and safe (to use) on Turkish people," Koca said, adding Ankara would use the data for licensing the vaccine.  He also said that researchers initially planned to announce the results after 40 people were infected, but that the findings showed the volunteers had minimal adverse effects after the shot and that it was therefore deemed safe. "Despite it being risky, we saw a very light picture where three people's PCR (COVID test) were positive, with no fever or respiratory problems... We can easily say that despite it being risky, those three people went through it very lightly," he said.

SHIPMENTS ARRIVE MONDAY

Turkey had agreed to buy 50 million doses of Sinovac's shot and receive delivery by Dec. 11 but the shipment was delayed. Koca said three million doses would arrive on Monday, adding that Turkey would vaccinate some nine million people in the first group, starting with health workers. Sinovac has also signed supply deals for its vaccine, called CoronaVac, with countries including Indonesia, Brazil, Chile and Singapore, and is negotiating with the Philippines and Malaysia. CoronaVac has been given to tens of thousands of people under an emergency use programme China launched in July targeting specific groups of high-infection risks. CoronaVac is based on traditional vaccine technology that uses inactivated coronavirus that cannot replicate in human cells to trigger an immune response. Vaccines developed by Pfizer/BioNTech and Moderna use a new technology called synthetic messenger RNA (mRNA) to activate the immune system against the virus and require far colder storage. Pfizer's treatment is the first fully tested COVID-19 shot to be administered, with rollout already under way in Britain and the United States Koca said Turkey would sign a deal with Pfizer/BioNTech for 4.5 million doses of their vaccine to be delivered by the end of March, with an option to buy a further 30 million doses later. On Thursday, Turkey's death toll from the coronavirus rose by 254 to 19,115, according to Health Ministry data, while the total number of COVID-19 infections rose by 18,102.