Dengue vaccine could increase dengue’s virulence in some settings

Mosquito sucking blood from host
A female Aedes aegypti mosquito acquiring a blood meal from a human. (Photo by James Gathnay, courtesy of CDC PHIL)

The first approved dengue vaccine may increase the incidence of more severe disease if used in populations with low dengue transmission

Researchers at the University of Florida and other institutions have created models highlighting the risks associated with the vaccine and the regions where implementing it would prove most effective without producing undue disease burden.

The dengue vaccine produced by Sanofi-Pasteur and licensed for use in six countries last year, may increase incidence of severe clinical outcomes, cautions a team of researchers at Imperial College, the Johns Hopkins Bloomberg School of Health, and the University of Florida in a paper published Sept. 2 in Science.

The development of this vaccine has been challenging because of the risk that vaccine-induced immunity could lead to more severe illness. In natural dengue infections, immunity induced by a prior dengue infection is an important risk factor for severe illness. Individuals experiencing their second natural dengue infection have a higher risk of severe disease compared with those experiencing their first infection. Vaccine developers have been acutely aware of the risk that vaccine-induced immunity could play a similar role in making some infections more severe.

Vaccine trials of the Sanofi-Pasteur vaccine conducted in over 30,000 participants from 10 countries across the globe have looked for evidence that vaccinated individuals could be placed at increased risk but have found little evidence. However, new analysis of publicly available trial data suggests that the vaccine could increase dengue disease at both population and individual scales if used in the wrong settings.

The researchers fit a large number of models to the vaccine trial data and compared the consistency of these models to the trial results. The models that fit the data best find that the vaccine acts like a silent natural infection in priming or boosting host immunity.

“The vaccine appears to act very much like a natural exposure but without illness,” said Isabel Rodriguez-Barraquer, MD, PhD, MHS, a research associate at Johns Hopkins Bloomberg School of Public Health and one of the lead authors of the article. “Vaccinated individuals who have been infected by dengue before receiving the vaccine acquire immunity similar to someone who has had two naturally acquired dengue infections. These people are at low risk of severe disease on subsequent exposure. In contrast, those people who have not been infected before receiving the vaccine look like someone who has been naturally infected only once after vaccination, and are at higher risk of severe disease than someone who has never experienced a dengue infection or received this dengue vaccine.”

The manufacturers of the vaccine have acknowledged that it does not work as well in those who haven’t been naturally infected before vaccination. This is consistent with the finding that the vaccine also tends to be less effective in young children who haven’t lived long enough to be infected. Data from the long-term follow-up of trial participants published last year showed increased rates of hospitalization among young vaccinees compared to the control group. The number of hospitalizations was small, but this observation highlights uncertainty about the action of the vaccine.

Partly based on these results, the vaccine is only indicated for children 9 years or older, in order to target people who are more likely to be seropositive. “Our results suggest that the impact of serological status on the efficacy of the vaccine appears to be much greater than the impact of age,” says Neil Ferguson, DPhil, MA, Professor of Mathematical Biology at Imperial College London and joint first author of the article. The vaccine is still under evaluation with long term follow-up still ongoing.

Given their best interpretation of the vaccine trial results, the researchers used models to forecast the impact of the vaccine if used regularly in various settings. The model predicts that the impact of the vaccine in any population depends strongly on the local transmission intensity and the age group(s) vaccinated. While vaccination in high transmission settings leads to modest decreases in dengue disease and hospitalization, vaccination in low-transmission settings may increase the incidence of more severe “secondary-like” infection and, thus, the numbers of people hospitalized for dengue. In moderate transmission settings, the researchers predict positive impacts overall but increased risks of hospitalization with dengue disease for individuals who are vaccinated before ever having a dengue infection.

“The key determinant is the transmission intensity of dengue in a population”, states Derek Cummings, PhD, Professor of Biology at the University of Florida and senior author of the study. “In places with high transmission intensity, most people have already been exposed to dengue at the time of vaccination and the vaccine has higher efficacy on average. However, in places with lower transmission intensity, where individuals haven’t been previously exposed, the vaccine can place people at risk of severe disease and overall, increase the number of hospitalized cases.”

Given the dangers associated with vaccinating someone who has never been exposed to dengue virus, the authors recommend that a point-of-care screening tool to identify those that have been infected in the past be used to improve the impact of the vaccine. “This test would need to be developed, but our results indicate that screening potential vaccine recipients could maximize the benefits and minimize the risk of negative outcomes,” said Cummings. If the cost of such a program were comparable to the cost of delivering a vaccine, then a combined screening and vaccination campaign could substantially increase the cost-effectiveness compared to the current three-dose strategy without testing.

Currently, World Health Organization recommends that countries consider introduction of the dengue vaccine CYD-TDV only in geographic settings (national or subnational) where epidemiological data indicate a high burden of disease.

Professor Ferguson added, “Our model results refine estimates of which places would see a decline in dengue incidence with large scale vaccination campaigns and which places should not implement campaigns at this point in time” said Ferguson. These results present the first published, independent predictions of the potential impact of vaccination taking into account recent data showing risk enhancement in young children.

The researchers’ results suggest that detailed epidemiological data should be collected and analyzed in any population considering wide scale vaccination programs. “Successful licensure of the first dengue vaccine is significant step forward for dengue control,” noted Cummings, “However, we should be careful in considering where and how to use it as there is still uncertainty about the exact effects of this vaccine.” The authors hope that their analysis can help inform policy-makers in evaluating this and other candidate dengue vaccines.

The work was funded by the UK Medical Research Council, the UK National Institute of Health Research under the Health Protection Research Unit initiative, National Institute of Allergy and Infectious Diseases (R01 AI114703) and National Institute of General Medical Sciences (U54 GM088491) under the MIDAS initiative, and the Bill and Melinda Gates Foundation.

“Benefits and risks of the Sanofi-Pasteur dengue vaccine: Modeling optimal deployment” by Neil M. Ferguson, Isabel Rodriguez-Barraquer, Ilaria Dorigatti, Luis Mier-y-Teran-Romero, Daniel J. Laydon and Derek A.T. Cummings is published in the journal Science.

Derek A Cummings

Derek A Cummings

Professor; EPI Associate Director For Education And Graduate Programs
Department: LS-BIOLOGY
Phone: (352) 392-1107