The rapid and ongoing geographic and epidemiological diffusion of infection by Zika virus (ZIKV) from October of 2013 (from French Polynesia to Brazil and to other countries of the Americas, with sporadic spreading in Europe and in the East), has long been signalled as global emergency for public health (article link February 3, 2016). By the large diffusion, the infection, although rarely aggressive, typically manifesting as a short-term fever, associated with maculopapular rash, headache, muscle aches, joints and / or non-purulent conjunctivitis, or often completely asymptomatic, however, arouses to serious complications for which it has been suggested a cause-effect relationship, ie the appearance of neurological disorders with increased risk of Guillain-Barré (article link 4 May 2016), fetal congenital microcephaly (link articles 29 February and 30 March 2016) and possible ophthalmologic sequelae (link articles April 1, 2016 and July 4, 2016). Yet little is known about the cellular targets and direct pathogenetic mechanisms or immune-mediated the ZIKV, as well as on those of immunological protection against the virus itself. These acquisitions are fundamental in perspective of the urgent need for a vaccine, in particular to protect pregnant women at risk of possible serious fetal complications. The problem is very timely, considering, for example, the large number of people from all over the world will travel to Brazil for the next Olympic games. It will not be available for such a big event, but a letter published online June 28 U.S. on the prestigious ‘Nature’ magazine highlights this theme, taking stock of the vaccine development strategies, effectively already experienced in other Flavivirus, such as yellow fever virus, Japanese encephalitis and dengue.
To develop preclinical models, from ZIKV strains isolated in the northeast of Brazil and Puerto Rico, later amplified in Vero cells (cells from the kidney of an African green monkey) to get lab ‘samples’, they were generated experimental models called respectively ZIKV-BR and ZIKV-PR, can reproduce in mice the typical clinical manifestations, including fetal microcephaly and other congenital malformations. They were so prepared for full-ZIKV strains, with the inner membrane and outer casing ( ‘PRM’ – ‘Env’), and mutant strains devoid of the ‘PRM’ region and / or the transmembrane region or casing structures (‘Env’). Were produced various vaccines using DNA plasmids coding for these deficient antigens and immunogenicity was evaluated in groups of mice that received a single immunization with 50 micrograms of each DNA vaccine intramuscularly at week 0, occurring antibody responses anti-‘Env ‘specific 3 weeks later. The DNA vaccine with
strain including the region ‘PRM-Env’ elicited the highest specific antibody response to the ‘Env’, indicating the importance of the pre-membrane as the entire wrap sequence region, while there has not been any antibody response specific for the region ‘PRM’. This same vaccine induced also specific neutralizing antibodies ZIKV after a single immunization with anti-‘Env ‘specific T-lymphocytes CD8 + and CD4 + response. To document the protective efficacy of these DNA vaccines were infected either unvaccinated mice (controls) and those vaccinated, at Week 4, through the intravenous injection of 105 viral particles ZIKV-BR and ZIKV-PR. Unvaccinated mice inoculated with ZIKV-BR have developed 6 days of viremia, with peak in the third day.
In mice vaccinated with a single dose of vaccine complete of the regions ‘PRM’ and ‘Env’, no viremia (<100 copies / ml) was found, as well as in vaccinated mice inoculated at week 8. The ZIKV-PR strain replied with slightly lower viremia the ZIKV-BR behavior, showing the same susceptibility to complete vaccine ‘PRM-Env’. The defective vaccines have not, however, provided adequate protection, although viral replication is impaired. The protective efficacy was correlated with the specific antibody titer for the Env ‘, as well as with that of the neutralizing antibodies ZIKV (threshold value> 10). To clarify the immunological mechanism of protection against inoculation of ZIKV-BR strain, IgG were purified from the serum of mice vaccinated with the full vaccine of the regions ‘PRM’ and ‘Env’. Passive immunoprophylaxis with intravenous infusion of various amounts of purified IgG generate antibody ‘Env’-specific classified into three levels according to the median, 2.82 (high), 2:35 (medium) and 1.87 (low). All mice with antibody titers greater than or equal to 2.35 were protected by the subsequent inoculation of ZIKV-BR, showing that protection can be mediated only by IgG elicited by the vaccine and confirming that the intensity of the antibody titer ‘Env’-specific correlates with the protective efficacy. On the other hand, only one of the 5 mice. On the other hand, only one of the 5 mice that received low doses of IgG ‘Env’-specific were protected, although viral replication was in all lower compared to controls. Finally, while eliminating T CD4 + and CD8 + lymphocytes in mice vaccinated with the full vaccine ( ‘PRM’ – ‘Env’) for 2 days before inoculation, this depletion did not annul the protective efficacy of the complete vaccine. This indicates that, at least in this model, the T lymphocyte’ Env’- specific responses are not required for vaccine protection, although it can not be excluded that the specific cellular immune responses to ZIKV they may be, however, useful in other contexts.
It ‘difficult to extrapolate directly from the results of these studies in mice a potential clinical efficacy of the vaccine in humans. Nevertheless, the robust protection observed in these experiments and the clear protective efficacy correlation with the measured antibody titres represent an important reference for the path to be followed for the development of a specific vaccine in humans.
These studies show that complete protection against ZIKV is effectively achievable with both DNA vaccines (complete with the regions ‘PRM’ that ‘Env’), both purified and inactivated viral vaccines. The intensity of the antibody titer ‘Env’-specific, which provides adequate protection in mice, should be easily reproduced in humans. Overall, therefore, these experimental conditions evoke a substantial optimism for the development of an effective anti-ZIKV vaccine and also safe in humans.
Nature. 2016 Jun 28. doi: 10.1038/nature18952. [Epub ahead of print]
Vaccine protection against Zika virus from Brazil
Larocca RA, Abbink P, Peron JP, Zanotto PM, Iampietro MJ, Badamchi-Zadeh A, Boyd M, Ng’ang’a D, Kirilova M, Nityanandam R, Mercado NB, Li Z, Moseley ET, Bricault CA, Borducchi EN, Giglio PB, Jetton D, Neubauer G, Nkolola JP, Maxfield LF, Barrera RA, Jarman RG, Eckels KH, Michael NL, Thomas SJ, Barouch DH.