Dengue vaccine could be adapted to combat zika virus

One option would be to insert a gene that codes for a key protein in zika virus into the dengue vaccine virus. Another would be to create an attenuated zika virus.

By Karina Toledo  |  Agência FAPESP – The technology developed to formulate Brazil’s dengue vaccine, supported by FAPESP and now in the final phase of clinical trials, can be adapted to create a vaccine against zika virus, said Jorge Kalil, head of Butantan Institute in São Paulo, Brazil, in an interview given to Agência FAPESP.

According to Kalil, one possibility would be to insert a gene that codes for a key protein in zika virus into the dengue vaccine virus. Another option would be to create an attenuated zika virus using a method similar to the technique deployed in developing the dengue vaccine.

Butantan Institute, which is a member of the recently created Zika Network, a task force set up by FAPESP that comprises some 40 research laboratories, has also begun working on the development of a protective serum that could be administered to infected pregnant women to combat zika virus before it harms the fetus.

During the interview, Kalil also spoke about the preparations required before the institute’s tetravalent dengue vaccine can be given to volunteers in the Phase 3 clinical trial scheduled to start later this month.

“We’re in the middle of a major outbreak of zika, but we mustn’t let that overshadow dengue, which is a persistent disease, continues to kill people in Brazil, and is expected to surge again this year,” Kalil said. Highlights from the interview follow.

Agência FAPESP – In December, you received the go-ahead from ANVISA, Brazil’s National Public Health Surveillance Agency, to start Phase 3 clinical trials of the institute’s dengue vaccine. What have you done since then?
Jorge Kalil – Since we received the green light from ANVISA on December 11, 2015, we’ve started making the final preparations required before immunization of the volunteers, which will begin this month. For example, we’ve had to produce more batches of the vaccine because what we had previously produced was close to expiring. We’d already prepared a batch in accordance with new rules issued by ANVISA for the production of vaccines for use in clinical trials. This required several changes to our production process. In addition, we’ve taken out insurance coverage for all participants and engaged a global clinical research organization (CRO) to manage the trial.

Agência FAPESP – What exactly will the CRO do?
Kalil – Clinical trials are highly complex affairs that involve large numbers of people. These CROs help train the staff of the participating centers, oversee the process to make sure the researchers comply with the specified procedure, and evaluate the quality of the data collected. None of that can be done by Butantan Institute because it’s an interested party and acts as a sponsor of the trial. We’ve engaged a global CRO because we mean to obtain international registration for the vaccine. Each of the 14 participating centers will have a lead researcher without any link to Butantan Institute.

Agência FAPESP – When exactly will immunization of the volunteers begin, and how will the trial be conducted?
Kalil – The exact date will be announced shortly by São Paulo State Governor Geraldo Alckmin. Immunization will begin in São Paulo, at Hospital das Clínicas, the teaching hospital attached to the University of São Paulo’s Medical School (HCFM-USP), followed by the other 13 centers. Altogether, we’ll vaccinate 17,000 volunteers and follow the response for up to five years. Before that, however, possibly within 12 months, we’ll be able to answer the most important question, which is whether the vaccine protects human subjects against dengue. How long that takes will depend on the incidence of the disease in the different trial locations during the months ahead and also on our capacity to immunize volunteers.

Agência FAPESP – Do you see the spread of zika virus in Brazil as a threat to the clinical trial of this dengue vaccine?
Kalil – Our main concern will be training the centers to diagnose accurately so that they distinguish between cases of dengue and zika. Apart from that, I don’t foresee any problems.

Agência FAPESP – Could the attenuated dengue virus used in the vaccine interact with the zika virus that’s circulating throughout Brazil?
Kalil – As yet, we have no data on this, but undoubtedly it’s something we’ll be looking out for during the trial.

Agência FAPESP – Is it possible to adapt the dengue vaccine so that it can be used for immunization against zika virus as well?
Kalil – One option is to use the same viral scaffold as in the dengue vaccine, which is a weakened form of the dengue virus itself, and insert the gene that codes for a viral envelope protein in zika virus. The viral envelope is the lipid bilayer that surrounds the capsid, the virus’s protein shell. We know that the neutralizing antibodies that protect us against these viral diseases target viral envelope proteins. Another option would be to create a vaccine using zika virus attenuated by a method similar to the one deployed to create the dengue vaccine. We plan to test several different possibilities.

Agência FAPESP – If so, would testing of the new vaccine have to start from the preclinical phase, or could it be fast-tracked?
Kalil – We’ll have to start over, but the process might perhaps move a little faster because of the similarity to what’s already been done. We’ve proved that the method is safe. Given the urgency, we could discuss fast-tracking with the public health authorities.

Agência FAPESP – Is Butantan Institute also working on a protective serum against zika virus?
Kalil – Yes, we’re growing the virus in cells in the lab with the aim of isolating specific antigens with which to immunize horses. We have to observe whether the animals produce significant amounts of neutralizing antibodies and, if so, isolate and purify these immunoglobulins in our production facility. This is similar to what we do to produce serums against toxins and poisons. The next step will be to obtain fragments of these horse immunoglobulins to act as neutralizing antibodies and inject them into women to combat the virus. We’ve started immunizing mice, and we’re developing tests to check that the antibody produced is of the neutralizing type, so the initial stages are under way.

Agência FAPESP – The World Health Organization (WHO) has declared a global emergency because of the rise in cases of microcephaly possibly linked to zika virus. Will this help speed up all the research?
Kalil – Absolutely. It will focus minds, promote more collaboration among scientists, and, above all, get more resources allocated to research. Ebola offers an example. Because an emergency was declared, research was fast-tracked, and the results of trials were assessed and approved far more quickly. This also depends on local regulators, but they should ratify the WHO’s decision.