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new analysis adds to concerns about the only vaccine available to protect against dengue, a nasty mosquito-spread disease colloquially called “breakbone fever” because of the painful achiness its sufferers endure.

The study, published in the journal Science, suggests the vaccine should really only be used in places where there is a lot of dengue activity and where most children who receive it will have already had at least one bout of the disease.

That’s because data from the studies used to approve the vaccine — called Dengvaxia, and produced by Sanofi Pasteur — showed a higher rate of hospitalizations for dengue three years after vaccination in young children who got the vaccine when compared to children who were unvaccinated.

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The increased risk, the study authors and others have said, appears to be for children who had had no previous dengue infections when they were vaccinated — in scientific terms, children who were seronegative.

“Our current estimates indicate that in all but the highest-transmission settings, use of this vaccine may lead to an increase in the risk of hospitalization for dengue in seronegative recipients even if the overall impact of vaccination is positive,” wrote the authors, from Imperial College London, Johns Hopkins Bloomberg School of Public Health, and the University of Florida.

“We predict routine vaccination will cause, at most, moderate … reductions in disease incidence, so it is important to set realistic expectations of impact for the policy makers and populations of countries likely to implement such policies.”

There are four different dengue viruses, named dengue 1 through dengue 4. Once you’ve been infected with one virus, it’s generally assumed you cannot contract that type again. But immunity to one of the viruses does not protect against the others.

In fact, having had one type of dengue increases your risk of having severe illness if you have a second infection. The most severe form of dengue — dengue hemorrhagic fever — can be fatal.

There has always been a concern that a dengue vaccine would increase the risk of severe disease, not lower it. And the studies Sanofi did to support its licensure bid for Dengvaxia seem to suggest that may be the case in young children who have not yet had dengue. The increased hospitalizations occurred in children between the ages of 2 and 5.

The vaccine is licensed for use in children 9 and older. Six countries have approved the vaccine: Brazil, El Salvador, Paraguay, Costa Rica, Mexico, and the Philippines, which earlier this year started using the product.

The World Health Organizations vaccine experts — known as the Strategic Advisory Group of Experts on Immunization — recommended earlier this year that if countries approve the vaccine, they should only use it in places where there is substantial dengue activity.

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Countries that want to use the vaccine should do studies in areas where they want to roll it out, ideally limiting its use to places where at least 70 percent of would-be recipients have had at least one dengue infection already, although prior infection rates of 50 to 70 percent would also be acceptable, the committee said.

Dr. Scott Halstead, a dengue expert who first flagged this problem, doesn’t think that position is safe enough.

“I do not believe … anybody should be going forward using this vaccine without testing the individual recipient to be sure they’re already seropositive. Because that’s the group that can benefit from this vaccine,” Halstead, a former US Army scientist who is semi-retired, told STAT.

Neil Ferguson, an infectious diseases modeling expert at Imperial College who is first author of the Science paper, agreed that would be the best way to use this vaccine.

Ferguson said a cheap, rapid test could be developed to check the status of each child due to get the vaccine. Children who had not yet had dengue would not be given the vaccine. And children who had already had a bout of dengue would only need one dose, not the three that Sanofi recommends — which would actually save money, Ferguson said.

Dr. Cesar Mascareñas, Sanofi’s global medical head for dengue, said the company is following the WHO’s position on when and how the vaccine should be used.

Mascareñas noted there is no sign the problem seen in the younger children happens when the vaccine is given to children 9 years and older. And he said the data on the younger children is not conclusive.

He also stressed that it is important to consider that the vaccine is the only medical tool against dengue, which the WHO suggests may infect nearly 400 million people a year.

There is no cure for dengue. Severe cases are treated with what’s known as supportive care — therapies that ameliorate the symptoms until the patient’s immune system can quell the disease.

The research was not funded by any one organization; the authors receive funding from a number of sources, including the UK Medical Research Council, the National Institutes of Health, and the Bill and Melinda Gates Foundation.

The six authors disclosed that three among them — including Ferguson — had advised Sanofi Pasteur on the implications of their findings, but had not taken payment for doing so.

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  • The only ones to survive the vaccine better are the ones who have had dengue before.
    Seems like the polio vaccine all over.
    I personally know a person with polio who was vaccinated 3 times before getting polio.
    I asked him what happened and he said that he was provided some BS like the refrigerator was not working.
    Sure. We know that polio cases rise in countries with a lot of polio vaccine.
    So we can expect that dengue cases shall rise after this vaccine is given to the population.
    Those who refuse to take it shall be given the vaccine at gunpoint and paid for by their taxes.
    Do some real research. Check the link and correlation between those who have AIDS and the probability that they were vaccinated with oral live weakened viruses. And also the correlation between polio probabilities after being vaccinated.
    You shall find a vey high correlation indicating that AIDS and Polio have a root cause as the polio vaccine.
    Same story for this dengue vaccine.
    The mosquito cannot survive in the Pakistani environment and they shall force the virus and not correlate with infections after vaccinations.

    Want to refute these statements or beg to differ. First check for any research on cases after vaccination. Then send them to me if you find any.
    Also minus the cases of infections after vaccination to see if vaccinations help or make it worse.

    http://www.cidrap.umn.edu/news-perspective/2016/07/contrary-dengue-vaccine-response-hints-possible-problems-zika

    Regards,
    Khawar Nehal

  • One sentence of this article is somewhat ambiguous, so I’d like to clarify that I am not of the view that Dengvaxia should ONLY be given to people who have tested seropositive. The paper I and my collaborators published in Science showed that individual testing would maximise the public health benefits possible from using the vaccine, but we also demonstrated that conventional vaccination programmes without testing could reduce dengue disease by 20-30% in high transmission intensity settings. However, due to the potential risks outlined in the article, policy makers need to be very cautious about deploying the vaccine in low transmission settings where the majority of recipients are likely to be seronegative. The WHO SAGE guidelines (which our work informed and supports) reflect this.

    P.S. Minor point in response to Dr Meera: Science is on PubMed. They just take a month or two to list new articles after they are published. And to clarify, the WHO SAGE guidelines are consistent with what our article recommends, in part because our work informed the creation of those guidelines.

  • First of all, the Science magazine is not a recognised, peer-reviewed medical-journal. Secondly, a search of (the US Library of Medicine’s) PubMed, that which catalogues articles published in recognised peer-reviewed medical-journals globally does not list any articles to the credit of one of the lead-authors, N. Ferguson (especially in the fields of Control and Prevention of diseases, vaccines and vaccine-research). Neither is any credited to I. Rodriguez-Barraquer – the other lead author, who is only listed to have made a comment on the original article based on the Phase III clinical-trials conducted by the manufacturer, and reported in the Lancet. Nothing else!!! Hence, the authors who published the original-articles in the Lancet and the New England Journal of Medicine are no less competent or credible experts, particularly in the fields of Preventive Medicine, Immunology, Paediatrics, vaccines and vaccine-research. Neither are the WHO’s Strategic Advisory Group of Experts (SAGE) on Immunization who, as the name conveys, are a high-powered group of experts on Immunization. I shall delve on the abstract of this article, thus: “The first approved dengue vaccine has now been licensed in six countries. We propose that this live attenuated vaccine acts like a silent natural infection in priming or boosting host immunity. A transmission dynamic model incorporating this hypothesis fits recent clinical trial data well and predicts that vaccine effectiveness depends strongly on the age group vaccinated and local transmission intensity. Vaccination in low-transmission settings may increase the incidence of more severe “secondary-like” infection and, thus, the numbers hospitalized for dengue. In moderate transmission settings, we predict positive impacts overall but increased risks of hospitalization with dengue disease for individuals who are vaccinated when seronegative. However, in high-transmission settings, vaccination benefits both the whole population and seronegative recipients. Our analysis can help inform policy-makers evaluating this and other candidate dengue vaccines.”, and, also on Rodriguez-Barraquer’s attempted explanation on their article titled “Dengue fever vaccine could cause severe illness at http://www.voanews.com/…/dengue-fever…/3490188.html

    My rebuttal:

    This article is deliberately misleading the public. Let me correct the mistakes.

    “People who live in dengue-prone areas frequently are infected more than once, but most suffer relatively mild symptoms, including fever.”, the article says. Actually, second and subsequent infections tend to be severe.

    “Large clinical trials involving approximately 10,000 children, ages 2 to 14 were conducted in South-east Asia (SEA) and in Latin America. Phase-three trials involved about 21,000 youngsters between the ages of 9 and 16.”, the article says. Actually, the Phase III clinical-trial in South-east Asia comprised of children aged 2 – 14, and that in Latin America comprised of those 9 – 16.

    “But as time went on, many of those who had been vaccinated, including the younger children, fell seriously ill with dengue.”, says the article. Actually, only children aged 2 – 5 in the SEA trial were found to have an increased incidence of Severe dengue in the first year after vaccination. This was not observed in the subsequent years. The researchers are unable to explain the phenomenon.

    “What seems to be happening with this vaccine is that those people who have never seen dengue in the past, that have never been infected in the past, if they get vaccinated, let’s say the vaccine acts like their first infection, right? So, if they ever get a second infection, or a true first infection, it would be more severe than it would have been, right? And that’s the concern”, the article quotes Rodriguez-Barraquer. Actually, that was a fear prior to the Phase III trial. But, the Phase III trial proved that did not happen.

    “That may explain why young children, many under the age of 9, were getting severely ill. They hadn’t lived long enough to get a first infection.” Actually, it only happened in the age-group 2 – 5. And as I had said, the researchers are unable to explain it.

    “But after further mathematical modeling, Rodriguez-Barraquer and her colleagues learned it was not only young children who were becoming sick after being vaccinated; it was also people who simply had never had dengue before.”, says the article. That is not true.

    “and what we suggest is that maybe having been exposed to dengue in the past, right, is more important than age itself.”, quotes the article. That is not true. As I had said, the researchers do not know the reason. Rodriguez is merely postulating.

    “The new analysis of the dengue vaccine was published in the journal Science.”, says the article. The Science magazine is not a recognized peer-reviewed medical-journal.
    “In countries with a high prevalence of the disease, Rodriguez-Barraquer said, the vaccine should not be a problem. Investigators concluded Dengvaxia can reduce severe illness and hospitalizations by 20 percent to 30 percent in such places.” says the article.

    The truth is, it was agreed by various researchers and authors who published the results in articles in leading medical-journals such the New England Journal of Medicine and The Lancet, and was agreed by the WHO’s SAGE and in the WHO Position Paper in July 2016 that the vaccine’s efficacies against hospitalized dengue illness were 72.7% and 80.8% among participants of all ages (under 16) and those ≥ 9 years, respectively. The corresponding efficacy estimates against severe dengue illness were 79.1% and 93.2% among participants of all ages (under 16) and those ≥ 9 years, respectively.

    Which means, the vaccine can actually save between 72.7 – 80.8% of hospitalized dengue illness, and 79.1 – 93-2 % of virologically-confirmed severe dengue illness.

    The WHO’s SAGE and the WHO Position Paper recommend that countries introduce the vaccine in mass-vaccination of the age-group 9 – 16 in areas with sero-prevalence of >70%. It is not recommended in areas with a sero-prevalence of 50% in this age-group.

    The antagonism to the new dengue-vaccine CYD-TDV (Dengvaxia), in the wake of my discussion above, is suspected mainly to be commercial.

  • Great article on harms vs. benefits of dengue vaccine. However, if you were to cover every healthcare intervention where harms likely exceed benefits, there wouldn’t be room for any other stories.

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