Abstract
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Best Use of an Attenuated Virus That Failed as a Vaccine Candidate?
Dengue virus (DENV) is a mosquito-borne pathogen, and DENV infections in endemic areas can be asymptomatic or result in symptoms ranging from mild rash to more severe pathologies that include a fatal form of hemorrhagic fever. Four strains of DENV have been identified, and previous infection with 1 strain usually induces protective immune responses, including strain-specific neutralizing antibodies, against reinfection with the same strain. However, should a previously infected individual be exposed to a different strain of DENV, those same antibodies can cross-react with the new strain and augment both infection and pathogenicity by facilitating the viral infection of antibody receptor-bearing cells. The biology behind these dynamic DENV-host interactions, complicated by the uncontrollable timing of exposures to different DENV strains, is a major reason that the scientific community does not yet have a safe DENV vaccine that is broadly protective against all 4 strains. In addition, there currently is no proven correlate of immune protection against DENV. As such, to show efficacy, any DENV vaccine challenge model must provide more biologically relevant data than just measurements of the degree and breadth of vaccine-induced immune responses to different DENV strains and antigens. A recent paper by Kirkpatrick et al 1 now presents data showing (1) the development of a safe, viable, and robust dengue human challenge model and (2) highly encouraging vaccine efficacy results based on that model.
One previously tested DENV vaccine candidate was based on a Kingdom of Tonga strain 2 viral isolate that, as a wild-type infection, induced only mild pathogenicity. To then test this isolate as a potential vaccine candidate component, the virus was attenuated by introduction of a 30-nucleotide deletion at the 3′ untranslated region of the single-strand, positive-sense RNA genome (rDEN2Δ30). However, when given as a live attenuated DENV to human volunteers, all recipients developed symptoms typical of a mild DENV infection, including viremia and rash. These sequelae were deemed unacceptable for using rDEN2Δ30 as a vaccine component for large-scale administration. However, it was recognized that rDEN2Δ30 might serve as a relatively safe challenge virus in a DENV human vaccine model for pilot studies because (1) the mild adverse reactions to rDEN2Δ30 resolved within days and (2) the viremia and onset of rash were quantifiable. In addition, because earlier studies suggested that strain 2 DENV may be more resistant to vaccine-induced protection than the other 3 strains, using some form of strain 2 DENV as a challenge virus to test vaccine efficacy limits made rational sense.
To evaluate the new DENV challenge model, a randomized double-blind placebo-controlled vaccine study was initiated. The vaccine itself, TV003, was an admixture of 4 recombinant live DENVs, attenuated in the same way as the challenge virus in that each had a deletion in its 3′ untranslated regions. Three of the vaccine components represented DENV strains 1, 3, and 4, and the fourth component was a chimeric version of the attenuated strain 4 DENV but expressed strain 2 DENV structural proteins. TV003 recipients were given a single inoculation, and all developed neutralizing antibodies to all 4 strains of DENV. Vaccine and placebo recipients were then challenged 6 months later with rDEN2Δ30: all control subjects developed viremia, and 95% developed a mild rash. In contrast, no rDEN2Δ30 viremia or rash was detected in the TV003 recipients, an indication that complete protection was achieved. While neutralizing antibodies probably played a key role, the authors speculate that cellular immunity also contributed to the observed protective effects. (Note: No data on this were presented, but retrospective testing for DENV-specific cellular immune responses is being performed.) Moreover, a phase 3 efficacy trial of TV003 is now underway in Brazil based on these highly encouraging data.