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expert reaction to preprint on the ChAdOx1 nCoV-19 vaccine and SARS-CoV-2 pneumonia in rhesus macaques

A preprint, an un-published non peer reviewed paper posted on bioRxiv, reports on the ChAdOx1 nCoV-19 vaccine and SARS-CoV-2 pneumonia in rhesus macaques.

 

Comments sent out on Monday 18 May

Prof Eleanor Riley, Professor of Immunology and Infectious Disease at the University of Edinburgh, said:

“Whilst the vaccine induced neutralising antibodies and vaccinated animals experienced less severe clinical symptoms than unvaccinated animals (good), the neutralising antibody titres were low and insufficient to prevent infection and – importantly – insufficient to prevent viral shedding in nasal secretions (worrying).  If similar results were obtained in humans, the vaccine would likely provide partial protection against disease in the vaccine recipient but would be unlikely to reduce transmission in the wider community.”

 

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

“The fact that the vaccine prevented pneumonia in all, and symptoms in some, of the vaccinated animals is encouraging – we know that many vaccines work because they prevent serious disease rather than preventing virus infection.  However, the amount of virus genome detected in the noses of the vaccinated and unvaccinated monkeys was the same and this is concerning.  If this represents infectious virus and a similar thing occurs in humans, then vaccinated people can still be infected, shed large amounts of virus which could potentially spread to others in the community.  If the most vulnerable people aren’t protected by the vaccine to the same degree, then this will put them at risk.  Therefore, vaccine efficacy in vulnerable populations and the potential for virus shedding in vaccinated people needs very careful monitoring.”

 

Prof Babak Javid, Principal Investigator, Tsinghua University School of Medicine, Beijing, and Consultant in Infectious Diseases at Cambridge University Hospitals, said:

“Media reports are emerging with regards to whether the Oxford-designed Covid vaccine candidate works in an animal (non-human primate) model works or not, and specifically, whether it is inferior to a recently published study in Science for the leading Chinese vaccine candidate.  The Oxford candidate works by using a modified chimpanzee virus to deliver a genetic copy of the SARS-CoV2 ‘spike’ protein, which the coronavirus needs to infect cells.  By contrast, the Sinovac vaccine is an inactivated whole coronavirus – very similar in some ways to the annual flu vaccine.

“The ‘gold standard’ of a vaccine candidate would be that it completely protects from infection (‘sterilising immunity’) and provides life-long protection in all immunised individuals.  However, we know that this is unlikely to be true for any Covid vaccine.  The question then becomes what are the optimal considerations for a Covid vaccine?  For me, it would be to protect the people most vulnerable to Covid disease – i.e. older individuals and those with pre-existing medical conditions, from severe Covid disease.  We know that inactivated vaccines tend to work less well in the elderly.  What we don’t know is whether the Oxford vaccine candidate, using a technology that has never been deployed in a licensed human vaccine, is better or worse than inactivated vaccines in this regard.  It could be either.

“One specific criticism of the Oxford vaccine results is that it did not protect the immunised animals from infection with SARS-CoV2 – virus could be recovered from swabs from all the immunised animals.  However, it did protect from disease (none of the immunised animals had pneumonia, compared with 2/3 of the unimmunised animals).  This isn’t without precedent.  In fact, the current whooping cough vaccine also works by preventing disease rather than infection.  The risks of such a vaccine are that immunised individuals, whilst protected themselves, would still be able to transmit infection to others, and if some of those are unimmunised, provoke disease in them.  This is certainly an important consideration if we are not aiming for universal vaccine coverage.  However, other, equally important considerations for an eventual candidate will be, first and foremost safety (in this regard, inactivated vaccines have an excellent track record), how long immunity would last, and crucially, as stated, whether immunity and protection is robust in the population most likely to become ill from Covid.

“Given the severity of the current Covid pandemic, it makes sense to evaluate a number of candidates in parallel (although I can’t see how we can evaluate 90!).  The best evidence of efficacy will be in phase II human studies in the target population in the midst of an ongoing pandemic, evaluated in ‘hotspots’ that haven’t brought the contagion under control.  From the data currently available, the Oxford candidate, if it proves to be safe in phase I studies, and has evidence of eliciting protective immune responses in humans, would be a reasonable candidate to proceed – alongside other leading candidates.  However, it should be stressed that we have no idea where (and if) an eventual ideal candidate will emerge from.  As such, talk of ‘vaccine nationalism’ is extremely dangerous and misplaced.  Covid represents a global and planetary threat.  International cooperation and solidarity will be required to overcome it.”

 

Comments sent out on Thursday 14 May

Prof Stephen Evans, Professor of Pharmacoepidemiology, London School of Hygiene & Tropical Medicine, said:

Is this good news?

“Very definitely.  It is one of the hurdles to be passed by the Oxford vaccine and it has cleared it well.  The most important finding to me is the combination of considerable efficacy in terms of viral load and subsequent pneumonia, but no evidence of immune-enhanced disease.  The latter has been a concern for vaccines in general, for example with vaccines against respiratory syncytial virus (RSV), and for SARS vaccines.  This was a definite theoretical concern for a vaccine against SARS Cov-2 and finding no evidence for it in this study is very encouraging.

Is this early preliminary data or a peer-reviewed paper?

“While it is a pre-print it comes from a very highly respected and competent group and is carefully planned research rather than just a happenstance finding, which is what some of the pre-prints are.  While peer review may improve the paper and some details will be altered, it is of high quality.

Do we know whether results in macaques will likely translate to results in humans?

“No we don’t know for sure, that’s why trials need to be, and are being, done in humans, but it is encouraging to see these results and suggests cautious optimism for the Oxford vaccine trial being done in humans.”

 

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:

“This publication describes two preclinical studies which investigated immune response to vaccination with the Jenner Institute SARS Cov2 vaccine in murine and primate models.  Single doses of the vaccine produced high quantities of neutralizing antibody in both species.

“One concern with vaccines against CoV species is the potential for antibody dependent enhancement of the disease pathology – this is one reason for the lack of a vaccine against the 2003 SARS CoV strain.  It is helpful to see that monkeys vaccinated with this SARS CoV2 vaccine did not have any evidence of enhanced lung pathology and that, despite some evidence of upper respiratory tract infection by SARS COV2 after high viral load virus challenge, monkeys given the vaccine did not have any evidence of pneumonia.

“These results support the ongoing clinical trial of the vaccine in humans, the results of which are eagerly awaited.”

 

Preprint (not a paper): ‘ChAdOx1 nCoV-19 vaccination prevents SARS-CoV-2 pneumonia in rhesus macaques’ by Neeltje van Doremalen et al is posted on bioRxiv.  This work is not peer-reviewed.

https://www.biorxiv.org/content/10.1101/2020.05.13.093195v1

 

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

www.sciencemediacentre.org/tag/covid-19

 

Declared interests

Prof Eleanor Riley: “No interests to declare.”

Prof Jonathan Ball: “Involved in a COVID-19 vaccine a vaccine project at the University of Nottingham and also working with an Italian group (who are also using chimp adeno vaccines.”

Prof Babak Javid: “None.”

Prof Stephen Evans: “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.  CEPI have provided funding to the Oxford vaccine work.  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.”

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).”

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