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Post by Admin on Sept 1, 2020 19:18:47 GMT
First batches of the Sputnik V vaccine against the coronavirus have been supplied to the medical institutions within the framework of the third post-registration phase of clinical trials of the preparation, Russian Healthcare Minister Mikhail Murashko told journalists on Thursday. Putin: Belarus will be one of the first countries to receive Russian coronavirus vaccine Earlier, the Russian Direct Investment Fund (RDIF) reported that post-registration clinical trials of Sputnik V, the first vaccine against the coronavirus, are planned in five other countries. Registered on August 11, Russian Sputnik V preparation became the first vaccine against the coronavirus worldwide that obtained state registration. The preparation was developed by the Gamaleya National Research Institute of Epidemiology and Microbiology of the Russian Healthcare Ministry and is produced jointly with the RDIF. In all, over 160 vaccines are being developed worldwide with over 30 of them being at the stage of clinical trials on humans.
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Post by Admin on Sept 6, 2020 20:29:21 GMT
Successfully rolling out a coronavirus vaccine by Nov. 1 will rely on clinical trials conducted at unprecedented speed, coupled with public release of research that shows it is both safe and effective, experts say. Reaction to the Centers for Disease Control and Prevention's letter to states to prepare for "large-scale" distribution of the vaccine in November — specifically, two days before the presidential election — triggered swift concern that political pressure could override commitments to safety. "I want to see the data," said Dr. Carlos del Rio, executive associate dean of the Emory University School of Medicine in Atlanta. "I need to show that there is true efficacy and safety." Doctors will insist on seeing the full data and will demand that the information come from those in the scientific community. "I want the physician scientists and not the political leadership to make these decisions," said Dr. Steven Nissen, a cardiologist at the Cleveland Clinic. "If it's made from the Oval Office," Nissen said, "there's going to be a lot of skepticism." New York Gov. Andrew Cuomo has already said he's suspicious of any vaccine that would be rolled out by early November. "It's going to be an Election Day miracle drug," Cuomo said during a call with reporters Thursday, adding that the New York State Department of Health would review safety and efficacy data before recommending the vaccine to residents. The necessary large-scale clinical trials needed to show that a vaccine works are underway, with tens of thousands of volunteers in the United States. Drug manufacturers have committed to produce millions of doses of their vaccines before they even know whether they work.
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Post by Admin on Sept 8, 2020 19:31:20 GMT
On Aug 11, 2020, Russia became the first country in the world to approve a vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The vaccine, which is based on two adenovirus vectors, was developed by the Gamaleya National Center of Epidemiology and Microbiology (Moscow, Russia). Its approval was announced by President Vladimir Putin. “I know [the vaccine] works quite effectively, helps to develop strong immunity, and has gone through all the necessary tests”, declared Putin at a cabinet meeting. Nonetheless, there are widespread concerns that the approval is premature. At the time of approval, the vaccine had not even started phase 3 trials, nor had any results on the earlier stage trials been published. Since then, the phase 1/2 results have been published in The Lancet. The vaccine induced a strong immune response in all 76 participants. Presumably these results were available to the Russian Ministry of Health. For regulators such as the US Food and Drug Administration (FDA) and the European Medicines Agency, however, data on immune response alone would not generally be an adequate basis for approving a vaccine. “Immune response might not be directly proportional to the degree of protection—you can only find this out in large-scale trials”, explains Peter Openshaw, professor of experimental medicine at Imperial College London (London, UK). The Russian vaccine is named Sputnik V, after the Soviet-era space programme. One person to have received it is the president's daughter. “She feels well, and the concentration of antibodies is high”, said Putin. “The main thing is to ensure unconditional safety and effectiveness of this vaccine in the future.” Mass production is expected to begin in September, 2020. Russia, which has seen almost 1 million cases of COVID-19, said that it would be able to provide 500 million doses of Sputnik V per year. “We have no idea whether this vaccine is safe or whether it works”, cautions Ashish Jha, Dean of the Brown University School of Public Health (Providence, RI, USA). “It is really worrying when people start to bypass the standard process we have for vaccine development.” Those behind the Russian vaccine have offered a combative response to such criticism. The official website was established with the stated aim to “provide accurate and up-to-date information about Sputnik V and to combat the misinformation campaign launched against it in the international media”. The vaccine is financed by the Russian Direct Investment Fund (RDIF), the country's sovereign wealth fund. Kirill Dmitriev, chief executive officer of RDIF, has complained that “instead of looking into the science behind the proven adenoviral vector-based vaccine platform Russia has developed, some international politicians and media chose to focus on politics and attempts to undermine the credibility of the Russian vaccine”. Large-scale clinical trials of the vaccine, involving over 40 000 people, were scheduled to begin in Russia in the last week of August. “A number of countries, such as United Arab Emirates, Saudi Arabia, the Philippines, and possibly India or Brazil, will join the clinical trials of Sputnik V locally”, noted the official website. Dmitriev has confirmed that Russia has received international requests for 1 billion doses of its vaccine. On Aug 26, 2020, Russian news agency TASS reported that the country would supply more than 2 million doses of Sputnik V to Kazakhstan. Openshaw points out that the places that have expressed interest in the vaccine are unlikely to start mass administration until they are assured that it is safe and effective. “There is a huge difference between Russia registering a vaccine within its own borders, which it is entitled to do, and international approval or WHO prequalification”, he said. Countries all over the world have preordered millions of doses of other prospective COVID-19 vaccines, with the rollout contingent on the results of the phase 3 studies. For example, the USA has purchased 100 million doses of Moderna's mRNA vaccine candidate and 300 million doses of Astrazeneca's adenovirus vector vaccine. Other countries might choose to make similar arrangements with the Gamaleya Center. Press reports have quoted the Azerbaijani Foreign Minister saying that the country was “ready to consider the possibility of purchasing a Russian vaccine against coronavirus after the completion of procedures for its recognition by the WHO”. According to WHO, as of Aug 28, 2020, nine vaccine candidates were in late-stage trials. These included separate adenovirus vector vaccines, a couple of mRNA vaccines, and several inactivated virus vaccines. There are plenty of vaccine candidates in earlier stages of evaluation. Experts are confident that at least one of the candidates will be successful. COVAX, a joint initiative between Gavi, the Coalition for Epidemic Preparedness Innovations, and WHO, aims to ensure any eventual vaccine is distributed fairly and equitably. 92 low-income and middle-income countries are eligible for support. The initiative is backing a range of vaccine candidates, including seven in clinical trials. Given the pace at which the candidates are moving through the stages of development, Jha wonders why Russia felt it was necessary to skip straight to approval. “I do not think it makes sense; the difference between doing things correctly and not doing things correctly is a matter of a few months”, he said. “It seems like a very small gain, and the middle of a pandemic is not the time to be cutting corners.” There has been speculation that the approval has been motivated by nationalism. Most countries would welcome the positive publicity generated by being the first to bring a vaccine against SARS-CoV-2 to market. The USA has also invoked the space age in its fight against COVID-19; it named its drive to secure 300 million doses of vaccine by January, 2021, Operation Warp Speed. If Sputnik V does not work or results in some kind of unforeseen adverse event in the phase 3 trial, that could affect the public perception of the vaccine process. Moreover, an ineffective product could actually worsen the pandemic—those who received the vaccine might stop taking precautions against contracting SARS-CoV-2. “There is a huge risk that confidence in vaccines would be damaged by a vaccine that received approval and was then shown to be harmful”, said Openshaw. A sizeable group of vaccine-hesitant people are already laying the groundwork on social media to discredit any potential COVID-19 vaccine. “We really do not want to make life any easier for those who are trying to undermine science”, said Jha. On the other hand, it is entirely possible that Russia will hold off vaccinating its general population until it has received favourable results from the phase 3 trial. In which case, the announcement of the approval of Sputnik V might amount to a political gesture, rather than a serious attempt to circumvent the standard process of vaccine development. The FDA has stipulated that a vaccine against COVID-19 should be at least 50% effective. Sputnik V might well meet this criterion. But until the phase 3 trial is completed and the results are made available, it will not be possible to make any judgement. “It is certainly not advisable for any vaccine to be used in an uncontrolled way before it has been through proper testing to determine whether the immune response it produces is actually protective, and there are no unexpected adverse events”, stressed Openshaw.
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Post by Admin on Sept 9, 2020 7:11:35 GMT
Safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine in two formulations: two open, non-randomised phase 1/2 studies from Russia
Denis Y Logunov, DSc † Inna V Dolzhikova, PhD † Olga V Zubkova, PhD Amir I Tukhvatullin, PhD Dmitry V Shcheblyakov, PhD Alina S Dzharullaeva, MSc et al.
Summary Background We developed a heterologous COVID-19 vaccine consisting of two components, a recombinant adenovirus type 26 (rAd26) vector and a recombinant adenovirus type 5 (rAd5) vector, both carrying the gene for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein (rAd26-S and rAd5-S). We aimed to assess the safety and immunogenicity of two formulations (frozen and lyophilised) of this vaccine.
Methods We did two open, non-randomised phase 1/2 studies at two hospitals in Russia. We enrolled healthy adult volunteers (men and women) aged 18–60 years to both studies. In phase 1 of each study, we administered intramuscularly on day 0 either one dose of rAd26-S or one dose of rAd5-S and assessed the safety of the two components for 28 days. In phase 2 of the study, which began no earlier than 5 days after phase 1 vaccination, we administered intramuscularly a prime-boost vaccination, with rAd26-S given on day 0 and rAd5-S on day 21. Primary outcome measures were antigen-specific humoral immunity (SARS-CoV-2-specific antibodies measured by ELISA on days 0, 14, 21, 28, and 42) and safety (number of participants with adverse events monitored throughout the study). Secondary outcome measures were antigen-specific cellular immunity (T-cell responses and interferon-γ concentration) and change in neutralising antibodies (detected with a SARS-CoV-2 neutralisation assay). These trials are registered with ClinicalTrials.gov, NCT04436471 and NCT04437875.
Findings Between June 18 and Aug 3, 2020, we enrolled 76 participants to the two studies (38 in each study). In each study, nine volunteers received rAd26-S in phase 1, nine received rAd5-S in phase 1, and 20 received rAd26-S and rAd5-S in phase 2. Both vaccine formulations were safe and well tolerated. The most common adverse events were pain at injection site (44 [58%]), hyperthermia (38 [50%]), headache (32 [42%]), asthenia (21 [28%]), and muscle and joint pain (18 [24%]). Most adverse events were mild and no serious adverse events were detected. All participants produced antibodies to SARS-CoV-2 glycoprotein. At day 42, receptor binding domain-specific IgG titres were 14 703 with the frozen formulation and 11 143 with the lyophilised formulation, and neutralising antibodies were 49·25 with the frozen formulation and 45·95 with the lyophilised formulation, with a seroconversion rate of 100%. Cell-mediated responses were detected in all participants at day 28, with median cell proliferation of 2·5% CD4+ and 1·3% CD8+ with the frozen formulation, and a median cell proliferation of 1·3% CD4+ and 1·1% CD8+ with the lyophilised formulation.
Interpretation The heterologous rAd26 and rAd5 vector-based COVID-19 vaccine has a good safety profile and induced strong humoral and cellular immune responses in participants. Further investigation is needed of the effectiveness of this vaccine for prevention of COVID-19.
Funding Ministry of Health of the Russian Federation.
Introduction COVID-19 was first reported in Wuhan, China, at the end of December, 2019.1 The disease is an acute respiratory illness ranging in severity from mild to severe, with death in some cases; many infected people are asymptomatic. Since the end of January, 2020, cases of COVID-19 have been reported in more than 200 countries around the world. On March 11, 2020, WHO described the spread of COVID-19 as a pandemic.2
The causative agent of COVID-19 is the betacoronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 can be transmitted in many ways, with the main route of transmission via contact with infected people (eg, by secretions, particularly droplets).3 As of Aug 15, 2020, there have been more than 21 million laboratory-confirmed cases of SARS-CoV-2 infection, and more than 750 000 deaths.1
Because of the rapid global spread of SARS-CoV-2 infection and the high mortality rate, development of a vaccine is an urgent task. Vaccination will restrict the spread of COVID-19 and reduce mortality. Intensive research and development of vaccines is currently underway in China, Russia, the UK, the USA, and other countries.4 According to WHO, on Aug 13, 2020, 29 candidate COVID-19 vaccines based on different platforms (vectored, DNA, mRNA, inactivated, etc) were being tested in clinical trials.4
Prevention of SARS-CoV-2 infection might be achieved by targeting the spike protein (glycoprotein S), which interacts with the ACE2 receptor and enables entry of SARS-CoV-2 into the cell. Blocking this interaction decreases viral internalisation and replication.5, 6, 7 Most vaccines that are currently in development target glycoprotein S as the main antigen. The structure and function of the SARS-CoV-2 glycoprotein S is similar to that of other highly pathogenic betacoronaviruses, such as Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus (SARS-CoV).8 Glycoprotein S consists of two subunits: S1 contains a receptor-binding domain (RBD), which interacts with the ACE2 receptor on the cell surface; S2 mediates the fusion of viral and cell membranes via formation of a six-helix bundle fusion core.9, 10 To protect against SARS-CoV-2 infection, it is important to form neutralising antibodies targeting S1 RBD, S1 N-terminal domain, or the S2 region; these antibodies block binding of the RBD to the ACE2 receptor and prevent S2-mediated membrane fusion or entry into the host cell, thus inhibiting viral infection.11, 12
When developing a vaccine (particularly during a pandemic), it is important to consider that a protective response must develop in a short time (eg, up to 1 month). Moreover, previous work on vaccines for MERS-CoV13 and SARS-CoV14 showed that both humoral and cellular (cytotoxic) immune responses are important to induce a protective immune response. To achieve these goals, one of the most attractive options is for vaccines to be based on recombinant viral vectors, which can induce humoral and cellular immune responses and form protective immunity after one or two doses.15, 16 Recombinant adenovirus vectors have been used for a long time, with safety confirmed in many clinical studies of various preventive and therapeutic drugs.17, 18, 19, 20, 21, 22, 23 Moreover, the long-term effects of vectors based on adenoviruses have been investigated,23 by contrast with newer methods that remain to be studied long term. For formation of a robust long-lasting immune response, a prime-boost vaccination is advisable, which is widely used with registered vaccines for diseases including hepatitis B24 and Ebola virus disease.25 When using vector-based vaccines, immune responses are formed not only to the target antigen but also to the vector component. As a result, the best vaccination scheme is heterologous vaccination, when different viral vectors are used to overcome any negative effects of immune response to vector components.25, 26, 27 Such an approach was successfully used with an Ebola virus disease vaccine developed in Russia and licensed in 2015.25
We designed a novel, heterologous adenoviral vector-based vaccine against SARS-CoV-2 suitable for prime-boost vaccination. The vaccine was designed with two recombinant adenovirus vectors and was developed as two formulations (frozen [Gam-COVID-Vac] and lyophilised [Gam-COVID-Vac-Lyo]). We aimed to assess safety and immunogenicity of both vaccine formulations and to compare the humoral immune response with that recorded in people who have recovered from COVID-19.
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Post by Admin on Sept 9, 2020 19:23:11 GMT
Methods Study design and participants We did two open, phase 1/2 non-randomised studies at hospitals in Russia (Burdenko Hospital and Sechenov University, Moscow, Russia). For each study, 120 healthy adult volunteers (aged 18–60 years) were preselected to be included in the volunteer register; all adults provided signed informed consent to be included in this database for study participation. Volunteers were screened by demographic data, had a physical examination and bodyweight measured, were assessed for vital functions (eg, blood pressure, pulse, and temperature), had a blood test for clinical and biochemical testing, were screened for infections such as HIV, hepatitis, and syphilis, underwent PCR for SARS-CoV-2 and had a test for antibodies to SARS-CoV-2, and had a urine test for drugs, alcohol, and pregnancy (in women). We included adult volunteers of both sexes with a body-mass index of 18·5–30·0 kg/m2, who had a negative PCR and negative IgG and IgM to SARS-CoV-2, and who had no history of COVID-19 or contact with patients with COVID-19. Volunteers had no infectious diseases at the time of vaccination and for 14 days before vaccination, and they did not receive any other vaccinations within 30 days of participation in the study. Based on the results of the preliminary screening, 100 volunteers were selected (50 for each clinical trial) for inclusion in the register of volunteers planning to take part in the study of vaccines against COVID-19. As soon as the volunteers were included in the register they began self-isolation.
All participants provided written informed consent. The two studies were reviewed and approved by appropriate national and local competent authorities, including the regulator (Department of State Regulation for Medicine Distribution, approval nos 241 and 242) and the ethics committee of the Ministry of Health of the Russian Federation.
Procedures The vaccine comprises two vector components, recombinant adenovirus type 26 (rAd26) and recombinant adenovirus type 5 (rAd5), both of which carry the gene for SARS-CoV-2 full-length glycoprotein S (rAd26-S and rAd5-S). Both components were developed, manufactured, and stored by N F Gamaleya National Research Centre for Epidemiology and Microbiology (Moscow, Russia) according to Good Manufacturing Practices. A full dose of the vaccine was 1011 viral particles per dose for both recombinant adenoviruses and all participants received full doses. The dose was set based on findings of preclinical studies (unpublished data). The vaccine was manufactured as two formulations, frozen (Gam-COVID-Vac) and lyophilised (Gam-COVID-Vac-Lyo). The frozen vaccine has a volume of 0·5 mL (per dose) and the lyophilised vaccine needs to be reconstituted in 1·0 mL of sterile water for injection (per dose).
The study of Gam-COVID-Vac was done at a branch of Burdenko Hospital, an agency of the Ministry of Defence. Both civilian and military volunteers took part in that study. Military personnel were contract employees (who received a salary for their work) and not individuals conscripted for compulsory military service. The study of Gam-COVID-Vac-Lyo took place at Sechenov University and all volunteers in that study were civilians.
In all cases, vaccines were administered intramuscularly into the deltoid muscle. During phase 1 of both studies, participants received one dose intramuscularly of either rAd26-S or rAd5-S and were assessed for safety over 28 days. Phase 2 of both studies began no earlier than 5 days after phase 1 vaccination, after an interim safety assessment had been done. During phase 2, participants received prime-boost vaccination, with one dose of rAd26-S administered intramuscularly on day 0 and one dose of rAd5-S administered intramuscularly on day 21. Injection-site reactions, systemic reactogenicity, and medication use to alleviate such symptoms were monitored for 28 days after the first injection (in phases 1 and 2) and at day 42 (phase 2 only).
No randomisation or special selection was done for phases 1 and 2. Participants were included as soon as informed consent was signed. Participants underwent clinical and laboratory assessments on days 0, 2, and 14 in phase 1 and on days 0, 14, 28, and 42 in phase 2. Laboratory analyses included complete blood and urine counts, alanine aminotransferase, aspartate aminotransferase, protein, bilirubin, total cholesterol, lactate dehydrogenase, alkaline phosphatase, prothrombin index, glucose, urea, and creatinine. Immune status was analysed on days 0 and 28 in phase 1 and on days 0, 28, and 42 in phase 2. Volunteers were in hospital for 28 days from the start of vaccination. Information on adverse events was recorded daily.
Determination of immunogenicity is described in detail in the appendix (pp 1–2). In brief, antigen-specific humoral immune responses were analysed on days 0, 14, 21, and 28 in phase 1 and on days 0, 14, 21, 28, and 42 in phase 2. The titre of glycoprotein-specific antibodies in serum was ascertained by ELISA. To test anti-SARS-CoV-2 IgG, we used an ELISA that was developed at N F Gamaleya National Research Centre for Epidemiology and Microbiology and registered for clinical use in Russia (P3H 2020/10393 2020-05-18). The ELISA measures IgGs specific to the RBD of SARS-CoV-2 glycoprotein S. The titre of neutralising antibodies was measured on days 0, 14, and 28 in phase 1 and on days 0, 14, 28, and 42 in phase 2 and was ascertained by microneutralisation assay using SARS-CoV-2 (hCoV-19/Russia/Moscow_PMVL-1/2020) in a 96-well plate and a 50% tissue culture infective dose (TCID50) of 100. Cell-mediated immune responses were measured on days 0, 14, and 28 after the first injection by determination of antigen-specific proliferating CD4+ and CD8+ cells by flow cytometry and by quantification of interferon-γ release.
To compare post-vaccination immunity with natural immunity that forms during infection with SARS-CoV-2, we obtained convalescent plasma from blood samples of 4817 people from Moscow who had recovered after COVID-19 (between March 29 and Aug 11, 2020).
Convalescent plasma was obtained from people who had had a laboratory-confirmed COVID-19 diagnosis, who had been recovered for at least 2 weeks, and who had tested negative by PCR twice. The average time from recovery to convalescent plasma collection was about 1 month. Convalescent plasma was collected from people who had had mild (fever ≤39°C without pneumonia) and moderate (fever >39°C with pneumonia) disease severity. Humoral immune responses were ascertained as mentioned above.
Outcomes Primary outcome measures were safety and immunogenicity of the COVID-19 vaccine. The primary outcome measure for safety was the number of participants with adverse events from day 0 to day 28 after vaccination in phase 1 and from day 0 to day 42 after vaccination in phase 2. The primary outcome measure for immunogenicity was change from baseline in antigen-specific antibody levels at 42 days (from day 0 to day 42), measured by ELISA. Secondary immunogenicity outcome measures were virus neutralising antibody titres (on days 0, 14, and 28 after vaccination in phase 1 and on days 0, 14, 28, and 42 after vaccination in phase 2) and determination of antigen-specific cellular immunity (specific T-cell immunity and interferon-γ production or lymphoproliferation) on days 0, 14, and 28 after vaccination.
Statistical analysis The sample size for both studies was calculated from previous clinical trials of a MERS vaccine27 based on the same recombinant viral vectors as used in our vaccine but carrying the MERS-CoV glycoprotein S gene. Preliminary results of a study of a MERS vaccine in which more than 100 people participated showed a seroconversion rate of 100%.27 When calculating the sample size for our study, we expected 99% efficiency, which required inclusion of 16 participants in each study. Considering the possibility of early dropout of volunteers, we decided that 20 volunteers should be recruited into the immunogenicity assessment group in phase 2 of each study. A total sample size of 76 (38 in each study) was expected to produce reliable data on adverse events.
All statistical calculations were done in GraphPad Prism 8. Normality of the data distribution was assessed with the d’Agostino-Pearson test. Paired samples were compared with the Wilcoxon test and unpaired samples with the Mann-Whitney U test. Correlation analysis was done with Spearman's test; the correlation coefficient r shows interactions between two datasets and takes values either from 0 to 1 (in the case of a positive correlation) or from –1 to 0 (in the case of a negative correlation). We used the Mann-Whitney U test to compare at various timepoints antibody titres, the level of proliferating CD4 and CD8 cells, and increases in concentrations of interferon-γ between volunteers receiving the two vaccines, and when comparing antibody titres in volunteers on days 28 and 42 after vaccination with antibody titres in convalescent plasma. We used the Wilcoxon test to compare data within the same group of volunteers at different timepoints (eg, when comparing day 0 to day 14).
These trials are registered with ClinicalTrials.gov, NCT04436471 and NCT04437875.
Role of the funding source The funder had no role in study design, data collection, data analysis, data interpretation, or writing of the report. All authors had full access to all data in the studies and had final responsibility for the decision to submit for publication.
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