| Interim Efficacy Results Reported for Third COVID-19 Vaccine Candidate. Interview with Wayne Koff, Ph.D. President and CEO Human Vaccines Project AstraZeneca announced results today from an interim analysis of its COVID-19 vaccine candidate that indicate the vaccine is 70% effective on average, according to an ongoing Phase III trial in the U.K. and Brazil. The vaccine candidate is the first of the viral vector platform vaccines to demonstrate efficacy, using an adenovirus that commonly infects chimpanzees to express the SARS-CoV-2 Spike (S) protein. This vaccine was developed in partnership with Oxford University and its spin-off Vaccitech. Both Pfizer/BioNTech and Moderna recently released interim efficacy results for their vaccine candidates, both of which are based on mRNA strategies for delivering vaccine antigens. According to AstraZeneca’s press release, the interim analysis conducted by an independent data and safety monitoring board was based on 131 COVID-19 cases that have occurred in the trial so far. Intriguingly, among a subset of volunteers (2,741) who received a half dose of the vaccine candidate followed a month later by a full dose, the interim efficacy was 90%. Whereas, the efficacy was 62% among volunteers who received a full dose of the vaccine candidate followed a month later by a second full dose. Based on these findings, the company announced it would seek approval from the Food and Drug Administration to also evaluate this half-dose regimen in its ongoing U.S. trial, which is currently only evaluating the two full-dose regimen. No serious adverse events, hospitalizations, or severe cases of COVID-19 disease were reported among vaccine recipients, according to AstraZeneca. Clinical trials of this vaccine are also ongoing in Japan, Russia, South Africa, and Latin America, with a targeted enrollment of up to 60,000 volunteers worldwide. HVP Editor Kristen Jill Abboud discussed these results and their interpretation with Wayne Koff, founding President and CEO of the Human Vaccines Project (HVP), in light of the two other recent reports of COVID-19 vaccine efficacy data. An edited version of the conversation appears below. This special issue also includes reactions from several experts in the field and a summary of AstraZeneca’s ongoing Phase III efficacy trial. Here we are with another interim efficacy result, this time with efficacy that differs based on the dosing regimen. What are your thoughts on this? How does this compare to the previous vaccine data released for the mRNA candidates? Again, this is really exciting to have another positive result from the AstraZeneca/Oxford vaccine, but we are still dealing with the same caveats, which is we don’t yet have the complete data regarding the breakdown in infections, the durability, or the efficacy in specific sub-populations. We eagerly await publications for all three of these vaccine candidates, which should happen relatively soon. We’re all anxious, as a field, to see the data in full and to be able to compare them. It’s a little early to understand any difference in efficacy between the different vaccination regimens for the AstraZeneca candidate and there are all the other questions regarding all three of the vaccines for which interim efficacy data have been reported, including the durability of the immune responses. I’m not sure what the mechanism could be for the efficacy varying by dosing regimen, but I would say that this really points again to the fact that we don’t understand a lot of the basics about human immunology or the best strategies for inducing protective immunity. For example, it would be ideal if we had an understanding of whether there are early markers of vaccine durability, and this is something we hope to be able to evaluate in the future. What are some of the key findings related to this vaccine candidate that differentiate it from some of the other platforms? The typical cold-chain storage—just being able to keep the vaccine stable in a normal refrigerator instead of at freezing temperatures—is a real advantage for this vaccine and should make deployment and delivery more feasible around the world. This alone should facilitate access. In the press release, the company also alludes to the fact that this vaccine may have the potential to block infection and not just prevent disease or serious disease, but again, without seeing the full data, we just don’t know. It is impossible to parse any differences based on just the press release. Given that this viral vector platform now seems to be effective as well, do you suspect that most or all of the COVID-19 vaccine candidates are going to work? If you make high enough titers of neutralizing antibodies against this virus in non-human primate studies, it appears that vaccine will likely be effective, with the caveat of course that to date, the correlate of protection from clinical trials has not been defined. We will have to wait to see if there are any differences that emerge between the candidates as we have more follow up and collect longer-term data. It is important to remember that for all of the candidates, this is only preliminary data based on a small number of infections and we will learn a lot more as these trials continue. Still, it is great news that we could have multiple effective vaccines relatively soon to deploy to help get this pandemic under control. Interview by Kristen Jill AbboudReactions from the Field  Soumya Swaminathan, M.D., Chief Scientist, World Health Organization“Encouraging news, especially as the world needs vaccines that are affordable and easy to deploy in a variety of settings. We do need to see the complete data to understand the differences in reported efficacy rate, as well as further safety data from ongoing trials.”  Seth Berkley, M.D., CEO, Gavi, The Vaccine Alliance“The AstraZeneca/Oxford vaccine is the first vectored candidate to report statistically significant results and the first vaccine that can be stored within the normal cold chain, making it easier to use within the existing immunization infrastructure in developing countries. The fact that large numbers of sites are producing it all bodes well for global supply. The differential results between half dose followed by full dose and two full doses is intriguing and awaits further analysis.”  Richard Hatchett, M.D., CEO, Coalition for Epidemic Preparedness Innovations“This is very encouraging interim efficacy data which indicates that we can expect this vaccine to have a significant impact on public health wherever it is used. Following the recent positive news about the mRNA vaccine candidates, it is terrific to see another approach to vaccine development also yielding such positive findings on an interim analysis. The world urgently needs multiple safe and effective vaccines to control the pandemic in a range of populations and settings, so the success of this viral vector vaccine would be a significant step towards that goal.”  Carlota Dobaño, M.Sc., Ph.D., Head of Malaria Immunology Group and Associate Research Professor, ISGlobal“We welcome with optimism the additional news on the significant prevention of COVID-19 obtained by a different type of vaccine that, like the mRNA formulations, has not yet been widely licensed for human use. While we await to review details on the most optimal schedule, the announced lower costs and refrigeration storage temperatures are encouraging, and should help to ensure more equitable distribution to the poorest communities worldwide. We will still have to wait to know how these initial promising vaccines perform in terms of long-lasting protection and safety, as well as across ages, geographies, and comorbidity groups.”  Bali Pulendran, Ph.D., Professor, Departments of Pathology, Microbiology, and Immunology, Violetta L. Horton Professor for the School of Medicine, Chemistry, Engineering & Medicine for Human Health (ChEM-H) Fellow, Stanford University“As the world anxiously awaits several billions of doses of safe and effective COVID-19 vaccines, today’s encouraging results from AstraZeneca provide hope that we will indeed have a portfolio of vaccines that immunize the planet against this scourge.”  Michel De Wilde, Ph.D., MDW Consultant“It is now clear that all candidates will work, we just need to wait a bit for longer term efficacy. For the Oxford/AstraZeneca candidate, it is surprising that such a small difference in dosage would have such impact. We will need to see the details on that.”  Gunilla Karlsson Hedestam, Ph.D., Professor, Department of Microbiology, Tumor, and Cell Biology, Karolinska Institute“Interim data from AstraZeneca’s Phase III trial are encouraging and add to the promising interim reports from Pfizer/BioNTech and Moderna. The next important steps are to await the data from the completed trials, including levels of induced immune responses, and to determine how long-lasting the protection will be for the different vaccine candidates. Until this is known, expectations should be realistic and recommendations should be set with caution in mind.”  George Siber, M.D., Co-founder and Member of Board of Directors, Affinivax, Inc., Adjunct Professor of Medicine, John Hopkins Medical School“To have a third vaccine with significant efficacy against COVID-19 is great news! It also raises significant quandaries, which will persist as additional vaccines complete Phase III trials. On the positive side, we have the first evidence of efficacy of another novel vaccine platform, viral-vectored vaccines. The quandary is that efficacy averaging 70% appears to lower than the mRNA vaccines and poses questions on how these vaccines are best deployed and explained. A further quandary is that a subgroup of 2,741 patients given a half dose prime followed by a full dose boost had 90% efficacy. This begs the question of whether two half doses may actually be optimal. We await further statistical analyses and detailed safety data.”Trial SummaryProtocol title: COV002: A Phase II/III Study to Determine the Efficacy, Safety and Immunogenicity of the Candidate Coronavirus Disease (COVID-19) Vaccine ChAdOx1 nCoV-19 COV003: A Randomized, Controlled, Phase III Study to Determine the Safety, Efficacy, and Immunogenicity of the Non-Replicating ChAdOx1 nCoV-19 Vaccine Study Sponsor: University of Oxford Collaborators: AstraZeneca Vaccine candidate tested: AZD1222 (also referred to as ChAdOx1 nCoV-19) Protocol summary: COV002 COV002 is a single-blinded, multi-center, randomized, controlled Phase II/III trial assessing the safety, efficacy, and immunogenicity of AZD1222 in 12,390 participants in the U.K. Trial participants to date are aged 18 years or over, are healthy or have medically stable chronic diseases, and are at increased risk for being exposed to SARS-CoV-2. Participants receive one or two intramuscular doses of a half dose (~2.5 x1010 viral particles) or full dose (~5×1010 viral particles) of AZD1222 or comparator, meningococcal vaccine MenACWY. Participants have blood samples drawn and clinical assessments for safety, as well as immunogenicity, at multiple timepoints up to one year post-vaccination. Suspected cases presenting with compatible symptoms were tested for virological confirmation by COVID-19 PCR. In addition, weekly swabbing is done for detection of infection and assessment of vaccine efficacy against infection. COV003 COV003 is a single-blinded, multi-center, randomized, controlled Phase III trial assessing the safety, efficacy, and immunogenicity of AZD1222 in 10,300 participants in Brazil. Trial participants to date are aged 18 years or over, are healthy or have medically stable chronic diseases, and are at increased risk for being exposed to SARS-CoV-2. Participants are randomized to receive two intramuscular doses of a full dose (~5×1010 viral particles) of AZD1222 or comparator, meningococcal vaccine MenACWY as first dose, and a saline placebo as a second dose. Participants have blood samples drawn and clinical assessments for safety and immunogenicity at multiple timepoints up to one year post-vaccination. Suspected cases presenting with compatible symptoms were tested for virological confirmation by COVID-19 PCR. The ClinicalTrials.gov identifier for COV002 is https://clinicaltrials.gov/ct2/show/NCT04400838. The ISRCTN identifier is http://www.isrctn.com/ISRCTN90906759 The ClinicalTrials.gov identifier for COV003 is https://clinicaltrials.gov/ct2/show/NCT04536051. Number of volunteers: COV022: 12,390 participants in the U.K; COV003: 10,300 participants in Brazil. Age groups: 18 and over in both trials, specific details of breakdown by age provided below. COV002:Adults aged 18 – 55 years (groups 4, 5, 6, and 11)Adults aged 56-69 years (groups 1, 7, and 9)Adults aged 70 years and older (groups 2, 8, and 10)Children aged 5-12 years inclusive (group 3) Please refer to ClinicalTrials.gov for information on groups. COV003: Adults from 18 to 55 years of ageAdults aged 56-69 years old (after review of safety data by DSMB in this age group in the U.K. trial)Adults aged 70 and above years old (after review of safety data by DSMB in this age group in the U.K. trial) Demographics: The global trials are evaluating participants aged 18 years or over from diverse racial and geographic groups who are healthy or have stable underlying medical conditions. Results summary: Note: only interim data of partial groups reported and this data is pooled from two clinical trials, COV002 and COV003 (description below does not include all groups, see clinicaltrials.gov for more info) Positive high-level results from an interim analysis of clinical trials of AZD1222 in the U.K. and Brazil showed the vaccine was highly effective in preventing COVID-19, the primary endpoint, and no hospitalizations or severe cases of the disease were reported in participants receiving the vaccine. There were a total of 131 COVID-19 cases in the interim analysis. One dosing regimen (n=2,741) showed vaccine efficacy of 90% when AZD1222 was given as a half dose, followed by a full dose at least one month apart, and another dosing regimen (n=8,895) showed 62% efficacy when given as two full doses at least one month apart. The combined analysis from both dosing regimens (n=11,636) resulted in an average efficacy of 70%. All results were statistically significant (p<=0.0001). Source: https://www.astrazeneca.com/media-centre/press-releases/2020/azd1222hlr.html Next steps: Data will continue to accumulate and additional analysis will be conducted. AstraZeneca will now immediately prepare regulatory submission of the data to authorities around the world that have a framework in place for conditional or early approval. The company will seek an Emergency Use Listing from the World Health Organization for an accelerated pathway to vaccine availability in low-income countries. In parallel, the full analysis of the interim results is being submitted for publication in a peer-reviewed journal. Previous data published: Phase I/II data for this vaccine candidate were published in The Lancet and data in non-human primates were published in Nature.FDA Advisory MeetingThe U.S. Food and Drug Administration announces advisory meeting on December 10th to discuss Emergency Use Authorization of COVID-19 Vaccines. Watch for coverage of this meeting in the COVID Report. |