Of Mice and Monkeys: Determining Protective Serological Titres in Model Zika Virus Infections

Developmental vaccines against emerging pathogens face many hurdles including determining what protective level of serological responses must be generated. Knowledge of a likely protective titre is critical where human challenge studies are not possible.

We have used an anti-zika plasma pool from convalescent patients (candidate serological reference reagent NIBSC16/320-14), infused into cynomolgus macaques and Type-1 IFN deficient mice to determine likely protective neutralising titres.

Anti-zika plasma was administered to a group of 4 macaques (single concentration) and groups of 8 A129 mice (4 group titration series) 24 hours prior to sub-cutaneous challenge with Zika virus PRVABC59. Plasma/sera samples were collected at regular intervals to track peripheral viremia and anti-zika antibody responses. FFPE tissues were collected at termination for histological analysis.

Immediately prior to challenge, human IgG was detectable in all infused animals. Within macaques the NT50 at this time was 250. All macaques that received plasma were protected against zika virus infection as determined by plasma/tissue qRT-PCR and IgM responses.

Titration within A129 mice gave a neutralisation titre of 110, above which mice were generally protected against zika infection. However this was not absolute as a small number of mice with high neutralisation levels were infected.

A protective NT50 of 250 has been identified for macaques and this further titrated in A129 mice to give a guide protective neutralisation titre of 110. The lack of protection in some mice with higher titres is currently unclear and studies are underway to compare their infection pathology with that of controls.