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expert reaction to two vaccine candidate studies: a phase 1/2 trial of the University of Oxford’s ChAdOx1 vaccine candidate; and a phase 2 trial of China’s Ad5-vectored COVID-19 vaccine candidate

Two papers on vaccine candidates for COVID-19 have been published in The Lancet. The first* discusses the results of a phase 1/2, single-blind, randomized controlled trial of the University of Oxford’s ChAdOx1 vaccine candidate, whilst the second¥ discusses a phase 2 randomised, double-blind, placebo-controlled trial of China’s Ad5-vectored COVID-19 vaccine candidate.

 

On both papers

 

Prof Danny Altmann, British Society for Immunology spokesperson and Professor of Immunology at Imperial College London, said:

“Two large, important, phase 1/2 clinical trials have been published in the Lancet. Both reports, from Oxford and from Beijing/Wuhan, document sizeable volunteer cohorts given an experimental vaccine whereby the SARS-CoV-2 Spike antigen is expressed in a construct derived from a modified adenovirus. There are some similarities and some differences. Both studies show a good safety profile. If the starting premise is that effective vaccines need to be able to safely induce decent levels of neutralising antibodies blocking virus entry and to induce a good frequency of antiviral T cells, each of these studies show that these goals are achievable. There are also some differences. The Beijing approach is based on the backbone of a conventional human, common-cold virus to which some people have pre-existing antibodies and they therefore make a lower response in some people to the vaccine because people have pre-existing antibodies to their vector, so may clear it before it has a chance to work properly. The Oxford approach overcomes this by deriving a chimp adenovirus platform to which humans have not made prior antibodies. While both vaccines raise a T cell response, the frequency of cells stimulated to respond by the Oxford vaccine look substantially higher, which would almost certainly be advantageous.  On the other hand, the Oxford approach is based on two injections (“prime-boost”), which would add considerably to logistic demands. Next steps, as the teams confirm, will be to establish durability and protective efficacy of these responses, including in people of different age-groups.”

 

Prof Ian Jones, Professor of Virology, University of Reading, said:

“The data from the phase I/II trial of the Oxford vaccine are as good as one could reasonably expect and confirm earlier use of the vector as a general vaccine platform. Trial participants developed the all-important neutralising antibodies, in most cases after one shot and in all cases after 2 shots. The outcome was measured in several ways to be sure that one assay did not give an overly generous answer but in fact all the methods agreed. The parallel Chinese study, which uses a human adenovirus instead of the chimpanzee adenovirus, also worked and despite the difference in the “vector” used, can be considered to re-enforce the case for an adenovirus vectored vaccine being a viable option for COVID-19.”

 

Prof Jonathan Ball, Professor of Molecular Virology, University of Nottingham, said:

The results of the Oxford chimp adenovirus vaccine candidate show that the vaccine is able to generate antibodies and T cells in humans and these persisted for several weeks. Whilst encouraging there is still a long way to go before we can herald the arrival of a successful coronavirus vaccine.

“It is unclear whether the levels of immunity can protect against infection – that’s what the larger ongoing phase 3 trials are designed to test.  Nor do we know if this vaccine can protect those most vulnerable to severe COVID-19 disease.

“Whilst the vaccine trialled in China used a different adenovirus to deliver the coronavirus protein, the fact that the immunity seen in the elderly included in the study was much lower than that observed in younger people is telling.

“At the very least a successful vaccine will either have to protect the elderly from serious disease or prevent less vulnerable people from becoming infected and spreading the virus. And at the moment, we don’t know which if any of the many vaccine candidates being trialled will achieve that.”

 

On the Oxford vaccine paper

 

Richard Torbett, Chief Executive of the Association of the British Pharmaceutical Industry (ABPI), said: 

“All over the world, pharmaceutical companies are working in partnership in the search for an effective Covid-19 vaccine and today’s announcement of progress in the UK is extremely positive.

“Developing a vaccine is an incredibly difficult challenge; the fact that there are multiple candidates in development is hopefully a sign that the hard work will ultimately pay off.

“But we must be patient.  Proving that a vaccine is safe and effective is a long process and we could still be many months away.”

 

Prof Stephen Evans, Professor of Pharmacoepidemiology, London School of Hygiene and Tropical Medicine (LSHTM), said:

“This paper is a clear description of a phase 2 trial of the “Oxford” vaccine. It is a reasonable sized trial for a vaccine phase 2 trial. It has encouraging results, but it is not the end of the road, far from it, but a vital necessary step towards an effective vaccine without significant harms.

“The press release gives a measured overview of the results reported in the paper. The results show that the vaccine has the desired and expected effects in terms of the immune response and does not have serious adverse effects seen in the numbers recruited so far. It is well-conducted, randomised and has an alternative vaccine (against meningitis) control group. The two-dose comparison is made largely within-person and does not have a comparison group so must have very limited conclusions.

“The key elements required to proceed to a Phase 3 trial are all there. The responses measured in the blood and the absence of serious harms indicate there is a possibility of an effective vaccine against Covid-19. It does not yet show that the disease is reduced or prevented, and this will not be easy to show until phase 3 trials have been completed in settings where the SARS Cov-2 virus is circulating at a high rate and people are getting clinical and severe disease.

“Until phase 3 trials have been completed, showing results that show a good level of protection against clinically relevant disease, this can only be regarded as potentially a good vaccine, but there are no good reasons for thinking the vaccine will be ineffective based on these results.

“For the vaccine to be really useful, we not only need the larger studies conducted where Covid-19 is still occurring at a high rate, but we need to be reasonably sure that the protection lasts for a considerable time. The results on efficacy have not been presented, and while they may only require 30 cases of Covid-19, it is entirely possible that rather fewer have been seen so far in the UK setting.

“It is also vital that those older than 55 (and in this report three quarters were aged under 45) are included and the phase 2/3 trial still ongoing will include such patients. The authors suggest that this vaccine could work well in more elderly patients, but we await data to see if this expectation is met.

“It is uncertain whether a booster dose will be needed, and the results on the small numbers having two doses suggests that could be beneficial in antibody response but not in T cells which may be more relevant.

“The authors set out these limitations clearly. The follow-up time is inevitably too short to be certain that the encouraging responses seen will be maintained over 6 months or a year.”

 

Prof Beate Kampmann, Professor of Paediatric Infection & Immunity and Director, The Vaccine Centre, London School of Hygiene and Tropical Medicine, said: 

“The immune responses to the ChAdOx1 nCoV-19 vaccine were measured both in terms of quantity and quality of antibody as well as for T cell responses to the spike protein in a subgroup of individuals. The preliminary findings look very promising with responses to the vaccine similar to what is seen post natural infection. Whether this is what’s needed to protect against infection and/or disease cannot be established with these early-phase datasets. Given that Phase I data from a number of studies are now being published, it would be helpful if the same standardised assays were used across all of international trials, so one could directly compare the results. Whether these immune responses are protective will remain to be established, but we are in the same boat with all of the vaccine candidates.”

 

Alex Harris, Head of Global Policy & Advocacy at Wellcome, said:

“This is just one crucial step but it’s very encouraging, and builds on the incredible global research effort during this crisis. To see promising results from several candidates in months is remarkable, but we must also be prepared for some candidates to fail in the later stages and be realistic about timeframes for manufacturing and rollout.

“Meeting the global demand of billions of doses will require more than one vaccine; it is in the best interest of all governments to work openly and collaboratively, pooling expertise and funding to access the broadest pool of promising candidates.

“We are very encouraged by the UK’s approach to securing access to a broad pool of vaccine candidates, which puts it in a strong position both in terms of access to vaccines for UK citizens and playing a leadership role in ensuring global equitable access.

“With limited supply globally, we must prioritise vaccine use for healthcare and essential workers, and those most vulnerable, so that sufficient doses are available for priority populations in all countries. This is critical for the first six to nine months of early vaccine availability, when global manufacturing capacity is unlikely to match demand. The UK is now in a strong position to make this a reality.

“COVID-19 is a global challenge: no one is safe until everyone is safe. The fastest, most effective way to beat the disease and end this pandemic is by securing vaccines, tests and treatments for those who are at most risk everywhere.”

 

Dr Doug Brown, Chief Executive of the British Society for Immunology, said:

“The initial phase 1/2 results of the Oxford vaccine trial, published in The Lancet today, are promising. The published data indicates that a single dose of the ChAdOx1 nCoV-19 vaccine is well tolerated with no serious adverse side-effects, although those who had the vaccine did report higher initial levels of fatigue and headache than controls, which was successfully treated with paracetamol.

“We are still in the early days of understanding what constitutes an effective long-term immune response against SARS-CoV-2.  This paper shows that the Oxford  vaccine elicited both neutralising antibodies and T-cell immune response against SARS-CoV-2 in the majority of patients after a single dose – this is a good first sign but we still have yet to understand whether these immune responses will have an effect if those individuals encounter the SARS-CoV-2 virus in the future.

“Developing new vaccines is a highly complicated process and success is by no means assured. The Oxford vaccine is only one of more than 150 vaccines against COVID-19 currently under development, 23 of which are in human trials. Although the results of this trial are an important step forward, they are not the end of the story. The researchers still have many more stages to go through before we can confirm that this vaccine is safe and effective for widespread use against SARS-CoV-2.

“The researchers working on this vaccine should be applauded for the monumental effort they have put in to move the science forward at such a fast rate. In the quest to find both vaccines and therapeutics against this novel coronavirus, we need to make sure that we continue to support our research community to maximise our knowledge of this disease.”

 

Prof Fiona Watt, Executive Chair of the Medical Research Council, which helped to fund the trial, said:

“It is truly remarkable how fast this vaccine has progressed, with our support, through early clinical trials, and it is very encouraging that it shows no safety concerns and evokes strong immune responses. There is a lot that we don’t yet know about immunity to the virus that causes Covid-19. However, it seems that both antibody and T cell immunity are important, and this vaccine triggers both responses. The much anticipated next milestone will be the results of the larger trials that are happening now to find out if the vaccine will protect people from the virus.

“The UK’s long-term investment in leading vaccine research enabled Professor Gilbert’s team to develop a vaccine to tackle a previous coronavirus outbreak, MERS, helping them to be one of the first in the world to start human trials for the COVID-19 vaccine. Many congratulations to all involved.”

 

 

* ‘Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial’ by Pedro Folegattti et al. was published in The Lancet on Monday 20 July

¥ ‘Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo controlled, phase 2 trial’ by Fen-Cai Zhu et al. was published in The Lancet on Monday 20 July

 

All our previous output on this subject can be seen at this weblink:

www.sciencemediacentre.org/tag/covid-19

 

Declared interests

Dr Doug Brown: “I’m a Trustee of the Association of Medical Research Charities”

Richard Torbett: “No declarations of interest”

Prof Stephen Evans: “No conflicts of interest. I am funded (1 day/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 or any grants obtained from them. I am the statistician to the “meta-Data Safety and Monitoring Board” for CEPI [https://cepi.net/]. I will probably be paid for my attendance at meetings and expenses for travel.”

Prof Beate Kampmann: “No conflicts of interest”

Prof Danny Altmann: “No conflicts of interest to declare”

Alex Harris: “No conflicts of interest”

Prof Ian Jones: “No conflicts of interest”

Prof Jonathan Ball: “I am involved in COVID vaccine studies.”

Prof Fiona Watt: “The Medical Research Council helped fund the trial.”

None others received.

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