June 28, 2016

expert reaction to study investigating two potential vaccines against Zika in mice

A study published in Nature reports the results of trials of two potential vaccines against the Zika virus in mice.

All our previous output on this subject can be seen here. The SMC also produced a Factsheet on Zika.

Prof. Adrian Hill, Director of Jenner Institute, University of Oxford, said:

Is this the first report of Zika virus vaccine protection in an animal model?

“I know of no prior report.

How big a deal is it?

“This is an encouraging first step in Zika vaccine design and pre-clinical testing. This new mouse model should be useful for comparative assessments of the large range of vaccine candidates now being designed.

How likely is it to work in humans?

“Very hard to say. The DNA vaccine technology has not been easy to get to work in humans. The inactivated virus vaccination approach might be better.

How far are we from a vaccine?

“The first vaccine trials will happen of prototype vaccines this year. Hopefully there will be better candidates tested in humans next year. We are years from a licensed vaccine.

“This is a straightforward study of the use of two established vaccine technologies in an attempt to design and test new Zika vaccines. The authors use a new mouse model with infection by two Zika strains including one from the ongoing Brazilian outbreak. The efficacy of the best vaccines was very high in mice, providing complete protection with a single dose. This is encouraging in that it suggests that a modest immune response, specifically of antibodies, is sufficient to protect against Zika in mice. This new mouse model could be very useful in allowing an initial comparative assessment of the likely potential value of the large number of Zika vaccine candidates being developed around the world.

“The route to a human vaccine will be more difficult. The DNA vaccine type tested is known to be a poor means of inducing antibodies in humans, and difficult to scale up to very large quantities, so better vaccine technologies are likely to be needed. The other approach, a traditional one of inactivating the whole virus and adding an adjuvant, was more immunogenic and protective. But this would require use of the pathogen itself to manufacture it.

“A separate challenge is the likelihood that immune responses to different but related viruses such as Zika and dengue may cross-react, as reported last week (Dejnirattisai et al. Nature Immunology doi:10.1038/ni.3515), sometimes with apparently adverse effects. It would be interesting to assess whether the antibodies induced by these Zika vaccine types increase infection by dengue viruses. If they do this could be a safety concern.

“But, overall, this report illustrates well the current rapid pace of Zika vaccine development and one US company (Inovio) reported recently plans to start a trial of their DNA vaccine technology for Zika very soon.”

Prof. Peter Openshaw, President of the British Society for Immunology, and Professor of Experimental Medicine, Imperial College London, said:

“In this very interesting study, the authors tested two types of vaccine against Zika virus infection in mice. They found that either a DNA vaccine or the conventional alum adjuvanted, formalin-inactivated vaccine induced antibody responses and protected against infection challenge.

“It’s reassuring that both vaccines worked in mice. The authors provide nice evidence that the levels of antibody produced are sufficient for protection and that depleting T cells has no discernible effect on protection once antibody has formed. They also establish what sort of levels of antibody might be needed for protection.

“There are some caveats, however. First, this is a study in mice; DNA vaccines that work in mice have a sorry history of not working in humans. I would have greater confidence in the classical inactivated vaccine working in humans. Second, the antibody levels were measured at 3 weeks, and the challenge with live virus was at 8 weeks. It’s not clear how long the immune response would be there for, and if a diminishing level of antibody might be protective or even disease-enhancing. The readout of infection is viral load and not disease severity – the two don’t always go together.

“These studies are a good step forward and give reason to be optimistic that vaccines might work in people. However, it is essential to move to human studies as soon as possible. By the time human vaccines are ready, many of the vulnerable population will have already been naturally infected. The purpose of vaccination will presumably be to protect travellers and those wishing to become pregnant. It will be vital to see how vaccines will work in such situations and how the practical and economic barriers to vaccine deployment can be overcome.”

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

“On the face of it, this is very good news and a significant step towards developing an effective vaccine to prevent Zika virus infection and the horrendous complications that this virus can sometimes cause.

“But we have to take these data in context, these were mice experiments and there is a long way to go before you can be sure that this vaccine candidate will perform in humans.

“These studies clearly show us that the vaccine is able to generate antibodies that protect the mice from Zika infection. However, it is also possible that the vaccine might produce antibodies that also recognise other viruses from the same family, like Dengue virus for example. The real worry is that these cross-reactive antibodies may actually enhance the infection of the other viruses, potentially causing very severe disease¹. This is especially worrying in regions where these other viruses circulate, for example Central and South America. It should be possible to work some of these issues out by further test-tube research and studies in animals. If the vaccines pass these tests then safety trials in humans would be the next step. If however, they do produce antibodies capable of enhancing infections such as dengue, then it may well be back to the drawing board.”

1: http://www.nature.com/ni/journal/vaop/ncurrent/full/ni.3515.html

Dr Derek Gatherer, Lecturer in the Division of Biomedical and Life Sciences, Lancaster University, said:

“With diseases spread by biting insects, such as Zika, standard quarantine measures are useless, so stopping an outbreak in its tracks requires a vaccine-led approach, as we are currently seeing carried out for Zika’s relative, yellow fever, in Angola and neighbouring countries. This new paper shows that the hopes expressed by NIH earlier this year for a vaccine trial by the end of 2016 might well be realistic.

“Both DNA vaccines, which have the advantage that they cannot cause the disease, and inactivated virus particles, which carry a small risk of disease if activation is incomplete, have now been shown to generate immunity to Zika infection in mice. Furthermore, antibodies extracted from the immunised mice can be used to protect other, unvaccinated, mice, proving that the vaccines stimulate Zika-specific antibodies.

“One important question, however, which is not addressed in this study, is whether the vaccines protect against all strains of Zika. Only Puerto Rico and Brazilian virus isolates were used, and both belong to the American section of the Asian variety of Zika. Ideally, we want a vaccine that gives global protection against Zika strains whether American, Asian or African. This would be expected to be feasible given the success of yellow fever virus across all varieties of that disease, so this prediction urgently needs to be confirmed for Zika. If it is, then the next step is to determine if monkeys display similar vaccine-induced immunity.  Since another recent paper¹ shows that a macaque monkey model of Zika infection has been established, this ought to happen soon. If monkeys are protected by the vaccine, and there are no signs of adverse effects, then human volunteer trials cannot be far away.”

1: ‘A rhesus macaque model of Asian-lineage Zika virus infection’ by Dawn M. Dudley et al published in Nature Communications on Tuesday 28 June 2016.

‘Vaccine protection against Zika virus from Brazil’ by Rafael A. Larocca et al. published in Nature on Tuesday 28 June 2016.

Declared interests

Prof. Peter Openshaw: “I have no relevant conflicts with respect to this story.” Prof. Peter Openshaw’s research is funded by the Wellcome Trust, the MRC, BBSRC and the European Union. He has received honoraria or consultancy fees from GSK, Janssen, and Mucosis BV.

Prof. Jonathan Ball: “No conflicts of interest.”

Dr Derek Gatherer: “No conflict of interest.”

No others received.