Experts positive about the future of a CMV vaccine

     
In Jan 2012 a group of experts convened in the USA to identify and discuss the key issues related to the development and evaluation of human cytomegalovirus (HCMV) vaccines. It was organised by four federal agencies of the equivalent of the UK Department of Health and included:
  • Leading researchers from around the world
  • Pharmaceutical companies interested in manufacturing and marketing a vaccine
  • Regulators (US: the Food and Drug Administration FDA, Europe: European Medicines Agency EMEA ) who will make the ultimate recommendation as to whether a vaccine is safe and effective
  • US Government agencies dealing with funding, decision-making and implementation
Conclusions were:
  • There are several possible candidates for a vaccine.
  • There are some gaps in the current knowledge base and issues to be resolved but these can be overcome.  A licenced CMV vaccine is possible for the future and there is strong support from the US Federal Government for achieving this
  • However more research is needed before there is clear evidence about whether it is safe and effective to vaccinate pregnant women who catch CMV for the first time, to try and prevent transmission to their unborn baby

There are a number of candidates for a potential vaccine

A vaccine is a way of priming the immune system to provide protection from disease, without subjecting the person to that disease.  There are two kinds of vaccines.  Passive vaccines provide ready-made immunity by given pre-formed antibodies.  Active vaccines give a preparation of antigens (a substance that is foreign to the body) to stimulate a protective immune response; (the name antigen comes from generates an antibody response). Many had thought that it would be impossible to make a vaccine against CMV. This virus works by evading the immune system, so sceptics feared it would also evade a vaccine.  An extra complication is that there are many different strains of CMV, and immunity to one strain does not protect you from being infected again with another strain.  With other viruses, once a person has become infected, he or she typically develops antibodies against it and will not become infected again. But it appears that having CMV does not make a person completely immune to future infections, although the immune system does give some protection. Despite these challenges there are a number of different active CMV vaccines that are showing promising results. These vaccines are in different stages of trials.  Phase I trials test the safety of a treatment on a small group of people and determine proper dosage.  Phase II trials then test the safety and effectiveness of a therapy in larger groups. Finally, regulators require large-scale Phase III trials before they will licence a vaccine for use.  CMV vaccines may be tested in Phase I and II trials on transplant patients before testing on groups of women who may become pregnant, to provide early evidence  about safety.
  • The first studies to produce promising results used an active vaccine with an antigen called glycoprotein B (gB).  Results of a phase II trial on women of childbearing age were published in 2009 (Pass et al). Women in the vaccine group caught CMV at about half the rate of women who received a placebo.
  • Studies of this same vaccine preparation in transplant patients have shown some interesting additional effects that are significant for tackling the risks of reinfection.  A Phase II study of transplant patients published in 2011 (Griffiths et al) showed that the vaccine increased CMV antibodies in those who already had natural immunity. This is important because these antibodies can help control infections like CMV which directly target the immune system.  It also had a significant impact on reducing re-infection in transplant patients who had already had CMV and received an organ from a donor who had also had CMV before.  This means that it boosted immunity to other strains.
  •   A phase II study of a different vaccine in transplant patients reported in Jan 2012 (Kharfan-Dabaja et al), strengthening the evidence that HCMV vaccines could be effective.
So, what are the next steps with vaccine development in the UK?  Developing a CMV vaccine is becoming a priority for the UK government just as it already is for the US government.  The decision about licencing a vaccine will be made by the Department of Health’s Joint Committee on Vaccination and Immunisation.  They are currently running a call for evidence amongst pharmaceutical companies to inform their plans for the year and have stated that “this year the committee is particularly interested in current developments of Cytomegalovirus immunisations”.  We'll give you more news when they report their plans for the year in June 2012.

Key stakeholders are now positive about the potential to develop a vaccine for congenital CMV

During the course of this event attendees discussed a number of specific issues including:
  • Which babies are most at risk of being born with congenital CMV?
  • What should the goal of a phase III trial be?  To reduce CMV infection rates in pregnant women, to reduce the proportion of children born with CMV or to reduce the health burden of congenital CMV?
  • Which group to target a phase III trial on?  Teenagers, women of childbearing age, toddlers?
  • Who should you ultimately aim to vaccinate?  Teenagers, toddlers or mums to be?  Males as well as females?
  • What proportion of the population would you need to vaccinate in order to wipe out CMV?
There is still a lot of research needed to get the answers to all these questions.  However the encouraging conclusion of this event was that it will be possible to develop and licence a vaccine for congenital CMV.  Stanley Plotkin, who developed the rubella vaccine and has worked on many other vaccines besides, set out his take on what we know about CMV “It was a wilderness many years ago, now it is well populated. I’m confident that a licenced CMV vaccine is in the future”. This will be fantastic news to all those parents who have not only struggled to come to terms with the consequences of congenital CMV but have also struggled to understand why more was not done to warn them of the risks before their child was born.  We now have the potential to control congenital CMV for future generations and save other families from the devastating consequences of this virus.

Evidence is less clear about whether it is safe and effective to give passive vaccines to pregnant women

Preliminary findings of an important study into a passive vaccine for pregnant women were released at the event.  With regular blood tests it is possible to identify if a pregnant woman has caught CMV for the first time and is therefore at risk of passing it to her unborn child.  Yet if there is nothing that can be done to reduce this risk then doing these tests only results in difficult, stressful choices for parents to be.  This is why researchers are investigating if it is possible to give ready-formed CMV antibodies to pregnant women in this situation to give them immunity and prevent the virus being passed on. A study in 2005 (Nigro et al) reported some very promising results by giving women an antibody preparation called immunoglobulin.  Many researchers  were concerned that the study didn’t meet the highest standards for a control group (where patients would be randomly assigned to receive either treatment or placebo and neither they nor the researchers would necessarily know what group they were in).  Three controlled studies were set up to verify the findings and Professor Revello set out the preliminary findings of her trial of 120 women in Italy.    The trial size was calculated on the basis of the how many women you would need in order to confirm the reduction in transmission rate (from 40% to 16%) that the Nigro trial had reported. Professor Revello found that there was a difference in transmission rates between those women who were given the immunoglobulin and those given a placebo. But unlike the Nigro study this difference was not significant i.e. it was small enough that it could have been due to chance rather than a definite effect of the immunoglobulin.  As her study was relatively small this doesn’t conclusively prove that it doesn’t have some sort of an impact.  However, it is unlikely that the effect of immunoglobulin could be as great as that reported by Nigro. We will now have to wait for the results of a much larger US study to really get to the bottom of whether this is a safe and effective treatment. The moral of this story? Its important to always do a bit of digging into the methodology that a trial has used as well as focussing on the headline results.  And for parents this is especially important if you are asked to take part in any studies.  It’s only if there is a properly designed control group that you can really tell if a treatment is safe and effective.   In the meantime, we eagerly await the next stage of this research.

Conclusion

A report of the event will be available later in the year.  The events were also filmed  and you can access the webcasts of day 1 and day 2 of the event (they are very long though – contact us if there are particular topics that you are interested in and we can let you know where to start watching!) The exciting conclusion of this event is a testament to just how far research but more importantly awareness and understanding of congenital CMV has moved on in the past decade.  When these same groups met in Atlanta in 2000 many more thought that a vaccine would not be possible.  With CMV now moving up the agenda our job in the next decade is to get to a stage where not only is a vaccine possible, but members of the public understand why we are campaigning to have their children vaccinated and are in support of a  vaccination programme for CMV in the UK. Caroline Star, CMV Action (checked for accuracy by Professor Paul Griffiths)

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