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Sanofi and GSK have announced a delay in their adjuvanted recombinant protein-based COVID-19 vaccine programme to improve immune response in the elderly.
Dr Gillies O’Bryan-Tear, Chair, Policy and Communications, Faculty of Pharmaceutical Medicine, said:
“It is disappointing that the GSK/Sanofi Covid vaccine, coming as it does from one of the power houses of vaccine science in the world, has not performed as well as hoped for in the phase 2 study: the immune responses in older people were insufficient to take the programme forward in its current form. GSK and Sanofi are working towards a new trial with an improved antigen formulation.
“It is a setback in the world’s efforts to control the pandemic, but underlies the importance – as attested to by Kate Bingham and the UK Vaccines Task Force this week – of having multiple options in addressing this pandemic. It also reminds us that pharma research is high risk and not always successful immediately. Fortunately technology platforms such as the mRNA/Oxford vaccines appear to have shown good results thus far which underlines the importance of many companies, large and small, using their expertise and continuing to innovate in this space. We have been extremely fortunate to have seen successful results from at least 4 vaccines to date, with more coming, and it’s important to acknowledge the scale of this achievement in such a short time.
“The platform being used by Sanofi/GSK is an older technology which relies on adjuvanting of the vaccine material to induce an adequate immune response. Older adults are known to have lower immune responses to such vaccines and this may be overcome by either repeated injections (prime- boost approach) or by increasing the antigen dose within each shot. In this case the companies seem to have decided to increase the antigen dose within the shot. The revised protocol is scheduled to start in February and will include a comparison to a different vaccine. This can then take advantage of the measured immune response to predict potential for clinical efficacy. Indeed, as more data is delivered on the relationship between immune response and clinical effect, it should be possible to move from requiring large scale clinical efficacy trials towards the use of ‘immune correlates’ of protection to decrease time required to bring a vaccine made using well established technologies to the market.”
Dr Andrew Garrett, Executive Vice President of Scientific Operations, ICON, said:
“It is interesting that the Sanofi GSK announcement describes the “proposed comparison with an authorised COVID-19 vaccine”. This is actually consistent with FDA guidance that states “If the availability of a COVID-19 vaccine proven to be safe and effective precludes ethical inclusion of a placebo control group, then vaccine could serve as the control treatment in a study designed to evaluate efficacy with non-inferiority hypothesis testing”. In other words, once a vaccine is approved, it is harder to justify the continuing use of placebo and an approved vaccine sets the bar from which others will be judged.
“As vaccines begin to be approved internationally, it is likely that newer studies will switch to being active controlled, although the actual choice of active control will need to be negotiated with the regulators, particularly if different approved vaccines have different efficacy and safety profiles. The FDA guideline references a non-inferiority margin of 10% for the efficacy endpoint. In other words, in the US an experimental vaccine will need to show that it isn’t 10% worse than the approved one – although that would only apply to new active controlled trials rather than any placebo controlled trials that are already underway.
“The FDA guideline also suggests that an acceptable approach would be to evaluate multiple vaccine candidates against a single placebo group to further increase efficiency. This use of a platform design relies heavily on strong collaboration across various stakeholders but would be similar to the approach adopted by the UK’s Recovery trial. The Recovery trial continues to evaluate treatments for COVID-19 and successfully demonstrated the efficacy of dexamethasone. The advantage of such a co-ordinated international approach would be to provide important head-to-head comparisons of vaccines and enable various combinations of vaccines (and dosing regimens) to be explored in an efficient manner. It may also be an attractive route for candidate vaccines that do not have the commercial resources and backing to conduct large scale clinical trial programs.
“The announcement today of the clinical trial programme to study the AZ & Oxford University / Gamaleya Research Institute vaccine combination is an example of the types of investigation that may be triggered in the future. What is clear, is that despite the welcome news over recent weeks, there is much to learn about the virus, the disease, the vaccines and the treatments. A coordinated international effort is called for to support the efficient evaluation of future vaccine candidates using a platform design.”
Reference: FDA. Development and Licensure of Vaccines to Prevent COVID-19. Guidance for Industry. June 2020. Sections C (Trial Design) and D (Statistical Considerations).
Prof Stephen Evans, Professor of Pharmacoepidemiology, London School of Hygiene & Tropical Medicine, said:
“This announcement is typical of what we might have expected as vaccine development is being carried out under intense public and media scrutiny for a pandemic vaccine.
“The first few vaccines to get to an interim analysis stage in phase 3 trials were unusual to have got that far without notable problems, and that is why most in the field were amazed at the results. This shows what we know, that it is not always easy to develop a new vaccine to the point of being used to prevent the disease. The Australian announcement and this one illustrate that getting a vaccine that shows efficacy in the relevant age (and other) groups is not a straightforward path; many uncertainties can persist.
“We do not have data that enables detailed evaluation, and it is possible that adjustment of doses and constituents of the vaccine could improve responses in the elderly, but again that is not guaranteed. It shows that we need to continue development of vaccines for Covid-19, because not every vaccine will get to the point of finishing phase 3 trials with demonstrated efficacy and lack of serious harm, and even those that do get there may find problems after their introduction that restrict or even prevent their widespread usage. It is encouraging that the system of development has checks such that progress at each stage is not automatic. We are certainly not at the end of the process for vaccines against Covid-19 and there will be things that surprise us as we progress. While any delay is disappointing, it shows that vaccines are not as simple to produce as the early successes might have implied.”
Dr Penny Ward, Visiting Professor in Pharmaceutical Medicine at King’s College London and Chair of the Education and Standards Committee of the Faculty of Pharmaceutical Medicine, said:
“The platform being used by Sanofi/GSK is an older technology which relies on adjuvanting of the vaccine material to induce an adequate immune response. Older adults are known to have lower immune responses to such vaccines and this may be overcome by either repeated injections (prime-boost approach) or by increasing the antigen dose within each shot. In this case the companies seem to have decided to increase the antigen dose within the shot. The revised protocol is scheduled to start in February and will include a comparison to a different vaccine. I presume this may be a clinically validated vaccination. This can then take advantage of the measured immune response to predict potential for clinical efficacy. Indeed, as more data is delivered on the relationship between immune response and clinical effect, it should be possible to move from requiring large scale clinical efficacy trials towards the use of ‘immune correlates’ of protection to decrease time required to bring a vaccine made using well established technologies to the market.”
All our previous output on this subject can be seen at this weblink:
www.sciencemediacentre.org/tag/covid-19
Declared interests
Dr Gillies O’Bryan-Tear: “I worked at GSK Biologicals in 2001-2002 leading the global clinical development of their paediatric vaccines. I currently work in a part time capacity for Scancell Ltd, a company developing cancer vaccines and a Covid vaccine.”
Dr Andrew Garrett: “I am employed by ICON which is a Contract Research Organisation. ICON provides pharmaceutical services to the pharmaceutical and biotechnology industries. ICON conducts clinical trials on behalf of Sponsors, including vaccine trials.”
Prof Stephen Evans: “No conflicts of interest. I am funded (one day per week) by LSHTM. They get funding from various companies, including Astra Zeneca and GSK but I am not funded by them, I have no involvement in obtaining funding from them and I am not an investigator on any grants obtained from them. I am the statistician to the ‘meta-Data Safety and Monitoring Board’ for CEPI. I am paid for my attendance at those meetings and will be paid expenses for travel if that occurs.”
Dr Penny Ward: “No COIs. I am semi-retired, but I am owner/Director of PWG Consulting (Biopharma) Ltd a consulting firm advising companies on drug and device development. Until July 2019 I was Chief Medical Officer of Virion Biotherapeutics, which was a company developing broad spectrum RNA therapy for the treatment/prevention of respiratory virus infections. Between December 2016 and July 2019 I served as Chief Medical Officer of Virion Biotherapeutics Ltd, a company developing antiviral treatments for respiratory viral diseases. Previous employee of Roche, makers of tocilizumab (anti IL6 antibody) and CMO of Novimmune, makers of empalumab (anti IFN gamma antibody).”