Dengue vaccine could make things worse: ‘We should be careful in considering where and how to use this vaccine’ | Outbreak News Today Outbreak News Today
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The only approved vaccine for dengue may actually increase the incidence of dengue infections requiring hospitalization rather than preventing the disease if health officials aren’t careful about where they vaccinate, new public health research published Sept. 2 in Science suggests.



Dengue typically causes a mild first infection but a far worse one if someone is infected with the virus a second time. There are four types of dengue virus, and it is thought that the body’s response to the first infection leads to more severe disease upon a second infection. This has long posed challenges to scientists developing a vaccine, who worried that any candidate that failed to protect fully could raise the risk of making people sick rather than keeping them well.

In their new study, researchers from the Johns Hopkins Bloomberg School of Public Health, Imperial College London and the University of Florida re-analyzed data from vaccine trials conducted in 10 countries with more than 30,000 participants as well as recently published data on the long-term follow-up of these participants. Using that data, they developed mathematical models to understand how a vaccine rollout would affect people in countries where transmission of the disease is high, moderate or low. They found that while the vaccine can reduce illness and hospitalization by 20 to 30 percent in places where there is high transmission of dengue, it may actually significantly increase illness and hospitalization if used in locations where there is lower transmission of the virus.

The vaccine, manufactured by Sanofi-Pasteur, has been licensed in six countries so far, and multiple countries are currently considering how to use this vaccine.

“In vaccines you hope for more than 30 percent success, but it’s the only vaccine available right now to slow dengue,” says Isabel Rodriguez-Barraquer, MD, PhD, MHS, a research associate at the Bloomberg School and one of the study’s lead authors. “If this vaccine is used correctly, many people could be spared illness and hospitalization from dengue. But we should make sure we only use it in places where our data suggest it will do more good than harm.”

The new research suggests that the vaccine acts very much like a natural infection but without making recipients sick. In those who have previously been infected with dengue, the vaccine acts like a silent second infection, stimulating the immune system without the more severe symptoms that may accompany a natural second infection. In those who have not yet been infected with dengue, the vaccine causes the immune system to recognize that a first dengue infection has occurred and then when exposed to dengue in a natural setting, the body reacts as if it is getting a second infection that may be more severe.

The manufacturers of the three-dose vaccine have acknowledged their vaccine does not work well in people who haven’t previously had a naturally occurring dengue infection before vaccination, the researchers say. The vaccine is not indicated for use in children under the age of nine because they are least likely to have been exposed to dengue.

Partly based on these findings, the World Health Organization is recommending that this vaccine be used only in areas where there is a known high burden of disease.

“We should be careful in considering where and how to use this vaccine as there is still uncertainty about its impact,” says Derek A.T. Cummings, PhD, a professor of biology at the University of Florida and an adjunct professor at the Bloomberg School and another of the study’s authors.

The authors hope that their analysis can help inform policymakers in evaluating this and other candidate dengue vaccines.

“Having a vaccine is a significant step forward for dengue control,” Rodríguez-Barraquer says. “However, this vaccine is a prime example of having to seriously weigh the risks and benefits.”

Dengue infects nearly 400 million people across more than 120 countries each year. Most survive with few or no symptoms, but more than two million annually develop what can be a dangerous dengue hemorrhagic fever, which kills more than 25,000 people each year. Dengue can cause a high fever, severe headaches, severe pain behind the eyes, rash and joint, muscle or bone pain. Dengue hemorrhagic fever occurs when blood leaks from blood vessels into other parts of the body, which can lead to failure of the circulatory system, shock and possibly death, without prompt treatment.

One thing that could help make decisions easier, the researchers say, would be a blood test that could identify those that have been infected in the past. Those who had been would get the vaccine; those who had not been would not be vaccinated.


  1. […] Dengue vaccine could make things worse: ‘We should be careful in considering where and how to use …  […]

  2. The manufacturer Sanofi Pasteur, subsequent to the CYD 14 and CYD 15 Phase III clinical-trials done in South-east Asia (SEA) and Latin America, did admit that in the SEA phase of the trial, it was observed that children aged 2 – 5 were observed to have an increased incidence (although a small number, but statistically significant) of Severe dengue in the first year after vaccination – which was not seen in the second and third years. This finding was also reflected in the several research-articles published in leading recognised peer-reviewed medical-journals globally, and also reflected in the WHO’s SAGE (Strategic Advisory Group of Experts on Immunization) Recommendation released in April 2016, and the WHO Position Paper released in July 2016. It was not observed in the children-subjects above 5 years old. According to both, “no other safety-signals were noted”.

    Yet, both the SAGE Recommendation and the WHO Position Paper gave a wider-margin of safety and excluded all children below 9 years in their Recommendation that countries consider introducing the vaccine in mass-vaccination programmes in areas of sero-prevalence (i.e. sero-positivity) of greater than 50% in the age-group 9 – 16, which both envisage will bring about 10 – 30% reduction in hospitalizations in the next 30 years – which, both believe would be cost-beneficial to the countries.

    The WHO Position Paper has since been released.

    And, there should not be any general apprehension and reluctance for the CYD-TDV to be introduced and used in any manner in endemic countries.

    The fact is that the WHO’s SAGE and the WHO Position Paper recommend that countries consider introducing the vaccine in the manner and under the conditions stipulated in the SAGE’s Recommendation and the WHO Position Paper. And besides that, there is ample evidence that the vaccine can be safely and efficaciously introduced on a purchase-for-use basis in the age-groups above 16 years, in the manner that has been argued and agreed.

    The truth is, no such recent studies were carried out in the US. There was a postulate and apprehension prior to the Phase III clinical-trials. But, the Phase III clinical-trials proved that did not happen, that the postulate was wrong, and there was no more reason for such apprehension.

    There is reason to believe that countries would hampered in their decision if they do not have data on dengue sero-prevalence, whether on a national nation-wide basis or by area, particularly endemic areas and dengue ‘hot-spots’.

    However, in a small sample of subjects within the Phase III trial in Malaysia, it was noted that Malaysian children in the vaccine-advocated age-group of 9 – 16 had sero-positivity greater than 50%. Hence, such a study (survey) need to be undertaken by the Malaysian Health Ministry first before the Ministry engages in mass-vaccination programmes as recommended by WHO. It would not cost the Ministry too much because it would only require appropriate sampling of the statistical-population to be studied, and each test is not likely to cost the Ministry more than RM 15.

    In the meantime, the Ministry must approve the vaccine for use on a purchase-to-use basis in the age groups above 16 years. Those to be vaccinated could be tested for sero-positivity prior to vaccination if these individuals deem it necessary. It will only cost about RM 15 each test, and it need not be done for each of the individual dengue-strains. And, it would not really matter whether they are sero-positive or not – those sero-positive would only have greater protection. That is all.

    “However the vaccine increased the rate of illness and hospitalisation in areas where the incidence of infection was relatively low.” some claim.

    That is not true. It only offered lesser protection in these.

    Therefore, we the Dengue Vaccine Advocacy Group, Malaysia strongly urge the Ministry here to register and approve the CYD-TDV (Dengvaxia) on a purchase-for-use basis first among those aged above 9 years, and strongly urge it to consider engaging in mass-vaccination of children in the 9 -16 years age-group in areas where the sero-prevalence of dengue is greater than 50% in that age-group, as recommended by WHO. As it is, there are about 300 Malaysians dying each year of the disease, and thousands more suffering debilitating Severe dengue – the survivors of which remain very traumatized coming back from the brink of death!

    For greater detail, please find below my rebuttal of an article against the new dengue vaccine titled “Dengue fever vaccine could cause severe illness at

    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.

    “The research by Neil Ferguson, published in the journal Science, analysed all publicly available clinical trial data for the vaccine.” Hence, no new such research/study/trial was conducted. Neil Ferguson’s claims are not more than his own interpretations of mostly the (results of) Phase II & III clinical-trials conducted by the manufacturers, Sanofi. The results of the Phase III trials, conducted in 10 countries, were also interpreted and utilised by the WHO’s Strategic Advisory Group of Experts (SAGE) on Immunization, who as the name implies, are no less competent and credible experts on Immunization, as Neil Ferguson and Rodriguez-Barraque – either individually, or as a group.

    In a search of (the US National Library of Medicine’s) PubMed, which catalogues Online all articles published in recognized peer-reviewed medical-journals globally, no articles (particularly on dengue vaccine) are credited to N. Ferguson, while I. Rodriguez-Barraque is only listed to have made a comment/statement on the original article, on the results of the CYD 14 and CYD 15 Phase III clinical-trials, published in the New England Journal of Medicine.

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