OPINION – Zika virus vaccine: perspectives

By Carolina de Andrade, Technical Analyst of Biominas Brasil

An emerging infection is happening in the Americas, an epidemic caused by Zika flavivirus, which is transmitted through the bite of the mosquito Aedes aegypti. The main clinical manifestations of Zika virus infection include acute onset of low-grade fever with maculopapular rash, arthralgia (notably small joints of hands and feet), or conjunctivitis (nonpurulent). However, the principal and more discussed consequence of Zika virus infection is the association with congenital microcephaly and fetal losses among women infected during pregnancy. Further investigation is ongoing and is widely discussed. According to preliminary analysis by the Brazilian authorities, a greater risk of microcephaly and abnormalities is associated with infection during the first trimester of pregnancy.

Prevention involves reducing mosquito populations and avoiding bites, which occur mainly during the day. Eliminating and controlling Aedes aegypti mosquito breeding sites also reduces the transmission of Zika, Chikungunya, and Dengue. Integrated control measures are required, involving actions in several areas, including health, education and environment.

Another model of prevention that has been discussed is the development of a vaccine against Zika virus. Jarbas Barbosa, director of the Brazilian National Health Surveillance Agency (ANVISA), in an interview to the journal “O Estado de Sao Paulo”, told that the Brazilian government has been discussing an agreement with the National Institute of Health (NIH) in the United States, for production of a vaccine. As he said, the NIH gathers centers that have already been working with Brazilian entities, under the development of a Dengue vaccine, by the Butantan Institute, which would facilitate the process. In December 2015, the Butantan Institute reported that it is preparing for the initiation of studies concerning a vaccine against Zika. The institution is organizing the research protocol to go through the ethics committee’s approval as well as the technical analysis of ANVISA. On February 11th, 2016, the signing of the first international agreement between the Evandro Chagas Institute (Pará – Brazil) and the University of Texas was annouced. Despite the different fronts, studies to find a vaccine against Zika are still embryonic and should only be considered as a long term solution.

Currently there is only one serotype of circulating Zika virus, unlike Dengue virus, which has four different serotypes. Recently, a tetravalent vaccine against Dengue virus was approved in Brazil by Sanofi Pasteur, a French company. There is no evidence that people infected with Zika virus are susceptible to re-infection, and thus, they would become immunized against the disease after the first infection. This would be the protection mechanism for a vaccine against Zika, which stimulate the production of antibodies against the virus.

A new vaccine against Zika virus needs to be approved as a new biological product, in accordance with Resolution – RDC No. 55 of December, 2010. The complete dossier, which characterizes the entire production process, demonstrating consistency in the drug manufacturing, as well as substantial evidence of clinical safety and efficacy as demonstrated by non-clinical and clinical phases I, II and III must be submitted to ANVISA. For the Dengue vaccine, for example, the registration dossier was submitted by Sanofi Pasteur on 03/31/2015, being prioritized the analysis by ANVISA on 04/27/2015. Approval was granted on 12/28/2015.

One of the ways to obtain fast track in a vaccine approval is to require the product registration with a finished clinical studies phase II and ongoing phase III, since a high therapeutic or preventive efficacy has been demonstrated and/or there is no other therapy or alternative drug comparable to that stage of the disease. However, the safety and efficacy of the vaccine should be monitored and continuously evaluated in Brazil, by the company\’s pharmacovigilance system.

According to an interview by Jorge Kalil, director of Butantan Institute, during a visit of the Minister of Health Marcelo Castro to the institution, the period to test the vaccine on monkeys is one year. From there, it would take 3-5 years to carry out the registration. For the prediction made by Kalil to be attended, however, it is necessary to conduct a series of scientific analyzes of the viruses that require long studies. For comparison, in normal conditions, a vaccine may take 10 to 12 years to be completely developed. The Butantan’s laboratories already maintain studies with Zika virus. The expectation of the Laboratory is to produce the vaccine from the attenuated Dengue viruses that will receive the gene responsible for coding the protein Zika. This method could help reduce the development time, given that the process of attenuation of a virus is quite long. It is important to highlight the need for prior authorization from the competent body, the National Biosafety Technical Commission (CTNBio), if any genetic modification in the attenuated virus of Dengue or Zika was performed. This authorization must be required even before the first submissions are made to ANVISA.

In parallel with the initiatives related to Zika virus vaccine, there is the development of other innovative technologies. The British company Oxitec, for example, was responsible for the development of genetically sterile male mosquitoes that instinctively find wild females. The puppies of these crossings die before adulthood. This alternative contribute to reduce the population of female and consequently the transmission of the disease. These mosquitoes are being tested in cities of Bahia and its use has shown good results. The Oswaldo Cruz Foundation (Fiocruz – RJ) conducts another important research. The institution is inoculating Wolbachia bacteria in the mosquitoes, aiming to incapacitate the insect to transmit tropical diseases. Males with Wolbachia that mate with native females result in non-viable eggs. The intersection between two mosquitoes with Wolbachia results in puppies carrying the bacteria. When only the female is infected, the generated eggs also carry the bacteria. Tests are being carried out in the city of Tubiacanga in Rio de Janeiro.

While the vaccine against Zika virus is being developed and the expectation of the same to enter into Brazilian market will still take considerable time, the association of innovative measures with the traditional practices to combat the Aedes Aegypti is fundamental.