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Source: United Kingdom – Executive Government & Departments

The phase 2 trial safety and immunogenicity data from the Oxford COVID-19 vaccine trial has been published in the Lancet, including data from healthy older adults.

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:

What is the difference between phase 2 and 3 – why is this different from the Pfizer announcement today?

“This is a phase 2 trial which is designed to explore preliminary safety profile and immunological reactivity following receipt of various doses of vaccine in individuals of different ages.

What is phase 2 designed to find out?

“The safety profile of the vaccine in otherwise healthy recipients and the immune response (antibody and cellular) to the vaccine among individuals of various ages.

What do we still need to know from this trial?

“Whether the vaccine protected recipients from COVID infection and/or illness post administration.

Why is data on older people so important?

“Older individuals are known to potentially have a lower immune response to most vaccinations – i.e. they produce lower levels of protective antibody and/or cellular immunity after receipt of vaccines against any infection than younger people do.  This might, in turn, reduce the efficacy of the vaccine in protecting older persons from the infection or illness which the vaccine is designed to prevent.

Does the data here show that the vaccine works in older people, or are we not there yet?

“The results of this study suggest that the immune response in older people (aged>70 years of age) was similar to younger people which in turn suggests that the clinical efficacy might also be similar.  Of note, the population of individuals recruited were older people without significant frailty, living independently in the community.  It would be useful to extend the study to explore immune response in older, frailer subjects living in care homes.  However as the vaccine was well tolerated in the study and was effective in similarly aged individuals, this suggests that it could be both well tolerated and effective in older and more infirm individuals in a care home setting.

Does the press release accurately reflect the science?

“Yes; and importantly it also shows that the immune response to the vaccine vector is not increased after the booster injection, which it is helpful to know.  The authors comment about a number of serious adverse events occurring during the trial and a list of these is given in the supplementary information which enables readers to understand that these were, for the most part, clearly non related incident disorders and unlikely to have been a result of the vaccine.  There was one reported case of pneumonia which might have merited particular discussion in the paper and particularly to know what the cause of pneumonia was in the affected patient.  We don’t know from the data given whether this person had had the vaccine or the placebo jab (‘adverse events’ mean things that happen to participants during a trial, and they are counted whether or not the participant had the vaccine or placebo).

Is this good quality research? Are the conclusions backed up by solid data?

“Yes and it is exhaustively reported.

How does this work fit with the existing evidence?

“It extends previous work and confirms that the vaccine is well tolerated and induces a prompt immune response: it remains to be seen if this results in protection from infection/COVID 19 illness.

Have the authors accounted for confounders? Are there important limitations to be aware of?

“They have acknowledged the limitations of the study design but these do not diminish the relevance of the reported results.

What are the implications in the real world? Is there any overspeculation?

“It appears that elderly individuals living in the community can expect to respond to the vaccine in terms of developing a possibly protective immune response and this bodes well in suggesting that the vaccine will eventually be shown to be effective in preventing illness in older people although this study does not currently provide information on the clinical efficacy of the vaccine in preventing infection/illness and we must await the phase III trial results for that information.”

Dr Gillies O’Bryan-Tear, Chair, Policy and Communications, Faculty of Pharmaceutical Medicine, said:

What is the difference between phase 2 and 3 – why is this different from the Pfizer announcement today?

“This is a peer reviewed publication in a major journal – the Lancet – of the phase 2 safety and immunogenicity (immune reaction) results from the Oxford/AstraZeneca Covid-19 trial, for which the phase 3 results are eagerly awaited.

What is phase 2 designed to find out?

“In phase 2 trials, fewer patients are enrolled than in phase 3, and the studies are designed to look for ‘proof of concept’ – does the vaccine do what it is intended to do in the intended patients?  This phase 2 study reported only on safety, and laboratory data – not efficacy data, as was announced by Pfizer and Moderna this and last week, who reported on much larger numbers of  vaccinated patients.

What do we still need to know from this trial?

“It will be important to know the efficacy results which will show how many people were protected from getting Covid illness – but the number of people in this trial is relatively small, and so the number of Covid infections may have been too low to report on this.  By comparison, the interim results from the Pfizer and Moderna trials reported on nearly 44,000 and 30,000 study patients respectively, which yielded 94 and 95 Covid patients respectively.

Why is data on older people so important?

“Immunosenescence – literally, the ageing of the immune system in older people – can lead to lower efficacy of vaccines in older people.  This is especially important as Covid has much higher lethality in older people.  One clue to this from the current study is that older people reacted less to the vaccine – fewer fevers, less injection site pain and swelling – but encouragingly, the immune responses in the older patients were indistinguishable from those in younger patients.  This suggests, but does not prove, that the protection against the illness will be similar in the elderly and the young.  There is support that older patients are protected by the spike protein vaccines from the further results announced by Pfizer from their large phase 3 trial, which showed similar efficacy – over 90% – in the elderly as in the young.

Does the data here show that the vaccine works in older people, or are we not there yet?

“We are not there yet – we need to see whether the immune responses in the older patients translates into protection.  With the two mRNA trials reported so far, there has been good correlation between immune responses and efficacy, so this is encouraging, though does not prove efficacy.  Those results are awaited from the phase 3 component of this study, which is awaited.

Is this good quality research?  Are the conclusions backed up by solid data?

“This is a well designed study by a well known Oxford vaccine research group.  As the authors of the accompanying editorial point out, the design was quite complex, and a similar design has been used by the Oxford triallists in the past with other treatments – for example, in some of the statin trials 20 years ago.  But it is no less robust for that, and the presentation of the data is first class – for example the bar charts of the side effects, colour coded by severity.  There is an accompanying large body of data in the Appendix.

How does this work fit with the existing evidence?

“These phase 2 results support other phase 2 data on the mRNA vaccines, which showed we can successfully induce robust immune responses to the spike protein on the Covid vaccine, using in this case an inactivated chimpanzee derived adenoviral vector vaccine.  Unlike the Sputnik V vaccine, which uses different adenoviral vectors (though the same antigen) for the two doses, this vaccine uses the same viral vector for both doses (called the prime and the boost dose).  This could cause issues with immune reactions to the viral vector itself, but there was no evidence within this trial that there were brisker immune responses to the vector after the second dose.  Whether this will cause lowered efficacy of the vaccine, we will learn from the phase 3 results.

Have the authors accounted for confounders?  Are there important limitations to be aware of?

“I was struck by the low number of ethnic minority patients in this study, and the authors did not seem to pick up on this in the discussion.  They also excluded frail patients, deliberately, although they are being included in the phase 3 trial I hope the larger phase 3 trial will have a more ethnically diverse patient population, and it should have, because it is being conducted in Brazil amongst other countries.”

Prof Deborah Dunn-Walters, Chair of the British Society for Immunology COVID-19 and Immunology taskforce, and Professor of Immunology at University of Surrey, said:

“Ensuring the safety and effectiveness of potential COVID-19 vaccine candidates is of the utmost importance.  We know that our immune systems change as we age, which results in a reduced ability to fight infections – one of the reasons that COVID-19 has taken such a high toll on our older population.  This decline in immune function in older adults can also result in a reduced response to vaccination.  As the British Society for Immunology recent report recommended, it’s imperative that all COVID-19 vaccine trials should prioritise research into understanding vaccine effectiveness and safety profile in older people, one of the groups of people most in need of protection against infection from SARS-CoV-2.  This includes examining how to ensure maximum vaccine effectiveness in older people by investigating dosing schedule, formulation, boosting and vaccination routes.

“It’s positive to see today’s study published in The Lancet running a phase II trial for the ChAdOx1 nCoV-19 vaccine in an older age group with a median age of 73.  While this is an ongoing study, the initial results are encouraging.  The vaccine appears to be well tolerated in all age groups, with older individuals reporting fewer side-effects.  At one month after giving two doses of the vaccine, all age groups showed a similar level of antibody response.  Some age-related differences in the cellular immune response were recorded which require further investigation.  However, if the immune measures recorded in the phase II part of this study correlate with protection from SARS-CoV-2, then we would expect positive outcomes from the phase III trial.

“Developing new vaccines is a highly complicated process and this study is just one piece of the puzzle.  Although the results of this phase II trial are an important step forward, they are not the end of the story and there is still much more we need to find out.  For example, how effective is this vaccine in older people who have other health conditions?  In order to thoroughly assess that the safety and effectiveness profile of this vaccine for widespread use against SARS-CoV-2, we now need to await the results of this vaccine’s much larger phase III clinical trial.  This is currently underway, involving thousands of participants, and will deliver more robust information on the safety and effectiveness profile of the ChAdOx1 nCoV-19 vaccine.”

Dr Michael Head, Senior Research Fellow in Global Health, University of Southampton, said:

“This is a peer-reviewed paper of a phase 2 clinical trial, which is reporting on slightly different aspects of COVID-19 vaccine research compared to the recent announcements about the phase 3 trials of the Pfizer and Moderna vaccines.

“The phase 3 studies are where we can measure the vaccine effectiveness, hence for example the reports that the Pfizer candidate has 95% effectiveness.  Here, with this Oxford-led vaccine, the phase 2 trials explore safety and whether the participants develop an immune response that may be protective in some way.  The research is well conducted and sizable for a phase 2 study including 560 participants.  For comparison, the Russia Sputnik trial reported 76 participants in their published study [see https://www.sciencedirect.com/science/article/pii/S0140673620318663?via%3Dihub]

“With the Oxford adenovirus vectored vaccine – there were no serious adverse events associated with the vaccine.  The observed side effects were minor, such as low-level pain around the injection site or a headache.  Thus, the data shows us that this candidate has a good safety record in this phase 2 trial.  The research also shows that an immune response was generated in all age groups, including in the cohort of participants aged >70 years.  Since elderly populations will be one of the priority groups to receive a vaccine when one is available, this is good news.

“This research is not an announcement that the vaccine is ready to be licensed and rolled out, but it is further promising research in the efforts to development a successful COVID-19 vaccine.”

‘Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults(COV002): a single-blind, randomised, controlled, phase 2/3 trial’ by Maheshi N Ramasamy et al. was published in the Lancet at 07.00am UK time on Thursday 19 November 2020.

DOI: 10.1016/S0140-6736(20)32466-1

Declared interests

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).”

Prof Deborah Dunn-Walters: “I have no conflicts.”

Dr Michael Head: “No conflicts of interest to declare.”

Dr Gillies O’Bryan-Tear: “No conflicts.  Former Head of Vaccine Clinical Development, GSK.  I am a pharmaceutical physician, semi-retired and have worked in a variety of fields, including oncology (cancer) drug development and vaccines development.  I have not been active in vaccine research for many years and have no current interests in or conflict with any of the Covid-19 vaccine research programmes.”

MIL OSI United Kingdom