Time elapsed between Zika and dengue virus infections affects antibody and T cell responses

Abstract

34The role of Zika virus (ZIKV) immunity on subsequent dengue virus (DENV) infections is 35 relevant to anticipate the dynamics of forthcoming DENV epidemics in areas with previous ZIKV 36 exposure. We study the effect of ZIKV infection with various strains on subsequent DENV 37 immune response after 10 and 2 months of ZIKV infection in rhesus macaques. Our results 38show that a subsequent DENV infection in animals with early-and middle-convalescent periods 39 to ZIKV do not promote an increase in DENV viremia nor pro-inflammatory status. Previous 40 ZIKV exposure increases the magnitude of the antibody and T cell responses against DENV, 41 and different time intervals between infections alter the magnitude and durability of such 42 responses-more after longer ZIKV pre-exposure. Collectively, we find no evidence of a 43 detrimental effect of ZIKV immunity in a subsequent DENV infection. This supports the 44 implementation of ZIKV vaccines that could also boost immunity against future DENV 45 epidemics. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61Zika virus (ZIKV) is a re-emerging mosquito-borne Flavivirus that has captivated the 62 attention of the scientific community by its explosive spread in The Americas 1 , and severe 63 neurological sequelae following infection 2-4 . ZIKV established itself in tropical and sub-tropical 64 regions that are endemic to other closely-related flaviviruses such as dengue virus (DENV). 65Both viruses belong to the Flaviviridae family and are transmitted by Aedes spp. mosquitoes. 66DENV is a global public health threat, having two-thirds of world's population at risk of infection, 67 causing ~390 million infections annually 5,6 . DENV exists as four genetically similar but 68 antigenically different serotypes (DENV1-4) 7 . Exposure to one DENV serotype confers long-69 lived immunity against a homotypic secondary infection. However, secondary infection with a 70 heterologous serotype of DENV is the major risk factor to induce severe DENV disease [8][9][10] . 71Due to the antigenic similarities between DENV and ZIKV, concerns have been raised 72 regarding the impact of DENV-ZIKV cross-reactive immunity on the development of severe 73 clinical manifestations 11,12 . It has been demonstrated that DENV-immune sera from humans can 74 enhance ZIKV infection in vitro 13,14 , and in vivo in immune-deficient mouse models 15 . However, 75 recent results from our group and others have shown that previous flavivirus exposure-76including DENV-may have no detrimental impact on ZIKV infection in vivo in non-human 77 primates (NHP) 16,17 and humans 18 . Moreover, these studies and others suggest that previous 78 DENV immunity may play a protective role during ZIKV infection involving humoral and cellular 79 responses 19-23 . On the other hand, little is known about the opposite scenario, the role of a 80 previous ZIKV exposure on subsequent DENV infection, which is relevant to anticipate the 81 dynamics of forthcoming DENV epidemics. 82The recent ZIKV epidemic in the Americas resulted in t...

Lying in wait: the resurgence of dengue virus after the Zika epidemic in Brazil

“…Furthermore, the dispersal velocity of these persistent DENV lineages peaked in 2016 and slowed with the decline of Zika and dengue in 2017. Together, our results indicate that DENV established cryptic transmission for more than five years before causing outbreaks in 2019, perhaps due to waning cross-protection provided by existing DENV and/or ZIKV population immunity 14,26 , a scenario that may have occurred across the Americas.…”

“…This reduction in susceptibility in 2017 and 2018 was likely a result of high DENV transmission over several preceding years, which may have provided some within and between DENV serotype protection (though we do not have sufficient data on serotypes to analyze). Based on this analysis, however, we cannot exclude a possible role for other factors, such as cross-protection conferred by ZIKV infection 14,26 , as also contributing to a reduction in dengue incidence in those years.…”

“…While the decrease in dengue incidence in 2017-2018 may have resulted from population immunity building during years of high incidence (Figure 1), exposure to other flaviviruses could have also played a role 14 . Recent studies demonstrated that immunity from previous ZIKV infections can neutralize subsequent DENV infections by all serotypes 26 , without exacerbating the severity of secondary heterologous infections by DENV 46 . This phenomenon could have led to higher numbers of asymptomatic or mild dengue cases 47 , resulting in low reporting of cases not only in Brazil, but also in most countries in the Americas, which experienced similar patterns of presumed low dengue cases after Zika outbreaks.…”

Immunogenicity and Efficacy of a Recombinant Human Adenovirus Type 5 Vaccine against Zika Virus

“…Lastly, using polyclonal sera from individuals who had naturally acquired ZIKV infection, we demonstrated that the antigens expressed by the hAd5-ZKV vaccine are recognized by the ZIKV-driven human polyclonal antibody response. Based upon our prior work as well as work by others, it can be said that the antigen-specific T cell and antibody responses can protect against ZIKV disease [ 19 , 21 , 22 , 64 , 65 , 66 ].…”

“…Current data from both naturally acquired human infection and mouse models of ZIKV disease indicate that protection from disease is multi-faceted (reviewed in [ 14 , 15 , 16 , 17 , 18 ]). Both small and large animal models of ZIKV infection have demonstrated that the Zika-specific CD8 + and CD4 + T cell response is necessary and sufficient to protect against a lethal ZIKV challenge [ 19 , 20 , 21 , 22 ]. As has been demonstrated previously for multiple flavivirus infections [ 23 , 24 , 25 ], ZIKV-specific polyclonal and monoclonal neutralizing antibody responses can protect mice and nonhuman primates from mortality and severe disease.…”