Approval of dengue vaccine could be advanced by two years

Researchers at Brazil's Butantan Institute have asked the National Public Health Surveillance Agency to authorize the final phase of clinical trials. The vaccine could be available for general immunization in 2016.

By Karina Toledo

Agência FAPESP – Researchers at the Butantan Institute in São Paulo, Brazil, have applied to ANVISA, the National Public Health Surveillance Agency, for permission to expedite the final phase of clinical trials of a dengue vaccine developed with FAPESP’s support.

According to the coordinators of the study, the development process could be shortened by up to two years if permission is granted. If the trials are successful, the vaccine could be available to ordinary Brazilians in 2016.

“We’re getting excellent results in phase two of the trials, and we want to speed up the process so as to have the vaccine ready for public use as soon as possible. The epidemic is so severe that the vaccine will be highly effective and clearly demonstrated,” said Jorge Elias Kalil Filho, Director of the Butantan Institute. Kalil told Agência FAPESP that he has already presented the idea to Marie-Paule Kieny, Assistant Director General of the World Health Organization (WHO).

During the 2014 Ebola epidemic in Africa, Kalil recalled, clinical trials of candidate vaccines were fast tracked in compliance with a regulatory mechanism whereby evaluations can be accelerated and two phases of trials can even be conducted concurrently in situations of epidemiological urgency.

So far, the dengue vaccine has been given to nearly 150 volunteers, with 150 others receiving a placebo, and there have been no reports of severe adverse reactions. Trials are ongoing to evaluate the patients’ immune response, but in Kalil’s view, there is sufficient data to guarantee that the vaccine is safe enough to advance to third-phase trials, originally planned for the end of 2015.

“This pioneering study by the Butantan Institute to produce a dengue vaccine, funded by FAPESP, is a research and development milestone for São Paulo. If we vaccinate people against the disease, we will effectively combat dengue, and many lives will soon be saved,” São Paulo State Governor Geraldo Alckmin told Agência FAPESP.

According to Alckmin, the vaccine must be licensed by “the Health Ministry and ANVISA, and the Butantan Institute will provide all of the information needed to verify the hypothesis of its approval at the earliest possible time.”

ANVISA issued a statement saying that the “feasibility of exceptional use of the dengue vaccine will have to be evaluated after we receive the request, depending on the data presented to justify early release.” The Health Ministry had not responded to inquiries by the time that this report went to press.

Clinical trials

The dengue vaccine is designed to be quadrivalent, i.e., to protect against four serotypes of the virus, and has been under development at São Paulo’s Butantan Institute since 2010, in partnership with the US National Institutes of Health (NIH).

This effort is funded by FAPESP through the project “Dengue: production of experimental batches of a tetravalent candidate vaccine against dengue,” coordinated by researcher Isaias Raw.

Clinical trials began in 2013 with the support of Fundação Butantan and BNDES, the national development bank, under the aegis of the project “Development of a quadrivalent dengue vaccine,” coordinated by Neuza Frazatti Gallina.

Phase-two clinical trials are currently under way at the Butantan Institute and the University of São Paulo’s School of Medicine, with the aim of evaluating the vaccine’s safety and its capacity to induce a lasting immune response in volunteers.

The effect of the vaccine will be compared with that of the placebo in a randomized double-blind trial, in which neither the researchers nor the volunteers know who receives the vaccine or the placebo.

“In stage A of phase two, we administered the vaccine to 50 volunteers aged between 18 and 59 years. None had had any prior contact with the virus. In stage B, now under way and scheduled to end in 30 days, we’re vaccinating 150 people in the same age group, some of whom have previously contracted dengue,” said Alexander Roberto Precioso, a researcher at the Butantan Institute.

Precioso also said that 13,000 surplus doses of the vaccine produced for phase two could be used as soon as permission is granted for phase three.

According to Kalil, the initial immunological results are “highly promising”, as are the results of the first phase-one and phase-two trials performed in the United States by the NIH.

“In all of the studies done so far, the immune response has been equally satisfactory and significant against all four serotypes after application of a single dose. This means we can move on quickly,” he said.

Opportunity

In addition to using the 13,000 surplus doses, which have a shelf life of 12 months, another reason to expedite the start of phase three, according to Precioso, is to take advantage of the fact that the current severe outbreak of dengue means that the virus is in wide circulation; therefore, the vaccine’s effectiveness can be demonstrated more quickly.

“Vaccinated volunteers must be exposed to the virus so we can be sure of the vaccine’s protective capacity. This could take longer in a period of low prevalence. However, given the epidemiological situation throughout Brazil, and especially in the southeast region and São Paulo State, the Butantan Institute is preparing a specific program with the aim of accelerating the trials,” Precioso said.

According to data collected by city governments using the Reportable Disease Information System (SINAN), the number of indigenous cases of dengue reported in São Paulo State between January and mid-March amounted to 56,959, corresponding to an incidence rate of 136 infections per 100,000 inhabitants. The number of reported deaths reached 67 in this period. In the 12 months of 2014, confirmed cases and deaths reached 196,800 and 90 respectively.

Precioso said that third-phase clinical trials will test the vaccine’s safety and efficacy in three different age groups: children aged 2-6 years, children and adolescents aged 7-17 years, and adults aged 18-59 years.

According to Precioso, if the results are positive, the vaccine may be licensed for use in 2016. Vaccination strategies and priority groups would then have to be discussed with the Health Ministry.

According to Gallina, coordinator of the project to develop the dengue vaccine and head of the pilot laboratory at the Butantan Institute, the current capacity amounts to 500,000 doses per annum. A new plant being completed will initially ramp up annual production to 12 million doses, after which production will be raised in stages to cover the entire Brazilian population.

Gallina explained that the process of strain construction, which attenuates the virus used in the quadrivalent vaccine, was performed in the United States.

Researchers at the NIH developed and tested a liquid formulation of the vaccine, which remained stable for only four hours under refrigeration conditions.

“Our challenge in the industrial development stage was to increase the vaccine’s yield and stability. To this end, we introduced a lyophilization process, basically freeze-drying the vaccine to produce a powder, which is more stable and has a 12-month shelf life,” Gallina said.

The following US-based researchers are also collaborating: Donald Francis, University of California; Anna Durbin, Johns Hopkins University School of Medicine; and Steven Whitehead, NIH.