DNA-immunisation with dengue virus E protein domains I/II, but not domain III, enhances Zika, West Nile and Yellow Fever virus infection

Abstract

Dengue virus (DENV), the causative agent of dengue disease, is among the most important mosquito-borne pathogens worldwide. DENV is composed of four closely related serotypes and belongs to the Flaviviridae family alongside other important arthropod-borne viral pathogens such as Zika virus (ZIKV), West Nile virus (WNV) and Yellow Fever virus (YFV). After infection, the antibody response is mostly directed to the viral E glycoprotein which is composed of three structural domains named DI, DII and DIII that share variable degrees of homology among different viruses. Recent evidence supports a close serological interaction between ZIKV and DENV. The possibility of worse clinical outcomes as a consequence of antibody-dependent enhancement of infection (ADE) due to cross-reactive antibodies with poor neutralisation activity is a matter of concern. We tested polyclonal sera from groups of female Balb/C mice vaccinated with DNA constructs expressing DI/DII, DIII or the whole sE from different DENV serotypes and compared their activity in terms of cross-reactivity, neutralisation of virus infection and ADE. Our results indicate that the polyclonal antibody responses against the whole sE protein are highly cross-reactive with strong ADE and poor neutralisation activities due to DI/DII immunodominance. Conversely, anti-DIII polyclonal antibodies are type-specific, with no ADE towards ZIKV, WNV and YFV, and strong neutralisation activity restricted only to DENV.

An interaction of Zika virus envelope fragments with serum antibodies derived from subjects after flavivirus infections

“…Исследования специфичности поликлональных антител, нарабатываемых в ответ на вирус денге у мышей, показали, что доминантной мишенью гуморального ответа является область домена III белка Е (рис. 1) [13]. В то же время у человека основной мишенью выступает регион шарнирной области, который располагается в доменах I и II [15].…”

Dengue: a growing threat requiring vaccine development for disease prevention

“…A possible A.D.E between members of flavivirus genus such as Zika virus (ZIKV) and DENV has been suggested due to the antigenic cross-reactivity of dengue antibodies with contemporary epidemic strains of ZIKV [45]. Whether dengue vaccination can have beneficial or detrimental impacts on ZIKV infection due to strong antigenic cross-reactivity between ZIKV and DENV is an important issue to be taken into account in the development of dengue vaccines [42,46,47].…”

“…Another variety of current dengue vaccine candidates involves recombinant DNA technology. There are recombinant subunit vaccines requiring expression systems such as plasmid DNA, heterologous vectors, virus-like particles based on the co-expression of the prM and E proteins or only displaying EDIII of the four serotypes, and purified recombinant viral antigens [34,43,[47][48][49][50][75][76][77]. Most dengue vaccine candidates are in preclinical studies or still in Phase I clinical trials.…”

Influência da Hidroquinona nas respostas imune humoral e celular induzida por vacina viral com proteína recombinante (Dengue)

“…Os arranjos dos três domínios dobrados em uma conformação de pre-fusão dimérica e um trímero de pós-fusão induzido por pH baixo agrupam-se em uma larga superfície hidrofóbica em uma extremidade do trímero pós-fusão (Rey et al, 1995;Modis et al, 2003;Bressanelli et al, 2004 (Figueiredo, 1999a), esses domínios são considerados fatores antigênicos primordiais do vírus (Campos et al, 2017).…”

“…Quanto à conformação estrutural, o domínio I possui uma estrutura β (Beta) localizada no centro do monômero da proteína do envelope e o domínio II, uma estrutura mais alongada (Modis & Clements, 2003;Oliphant et al, 2006). Apesar de todos os domínios serem alvos de anticorpos neutralizantes, até hoje o domínio III é o que mais possui epítopos descritos Campos et al, 2017). Esses domínios também possuem uma alta reatividade cruzada com outros flavivírus, como o Zika vírus Campos et al, 2017).…”