Abstract
BackgroundPregnant women from developing countries are at high-risk of hepatitis E-associated high mortality and constitute priority population for vaccination. So far, candidate vaccines have not been evaluated during pregnancy. We evaluated our vaccine candidate, recombinant Neutralizing Epitope protein (rNEp) encapsulated in liposomes, in pregnant mice.MethodsA single dose (10 μg) of the formulation was administered intramuscularly on day 7 of pregnancy. Titres of serum IgG antibodies to hepatitis E virus (IgG-anti-HEV), levels of cytokines and biochemical parameters were determined. Spleens were harvested from pregnant and non-pregnant mice for immunophenotyping (flow cytometry), cytokines (cytometric bead array, CBA) and gene expression of immune response genes (Taqman low density array, TLDA). Histopathology studies of spleen, liver, kidneys, brain and muscle was carried out.ResultsThe vaccine was well-tolerated during pregnancy as evidenced by histopathology and serum biochemical parameters. Anti-HEV titres were significantly higher in the pregnant balb/c and C57BL/6 mice (3592 ± 802 and1016 ± 138 respectively, than in non-pregnant groups (634 ± 191 and 320 ± 55 respectively, p < 0.001 for both) suggesting that the higher antibody response in pregnant mice was independent of the genetic makeup of the host but immunogen-driven. Pups receiving vertically transferred antibodies developed lower anti-HEV antibodies (p < 0.05) when immunized with the formulation after seronegativity than in the age-matched mice without such antibodies. In non-pregnant mice, a Th1 response and discordance between splenic and serum cytokines was evident while in pregnancy, a Th2 bias was observed irrespective of immunization. Increased CD19 levels correlated with higher anti-HEV titres in pregnant mice.ConclusionThe single dose of the vaccine was safe and highly immunogenic in pregnant mice. Degree and type of immune response to vaccination during pregnancy is immunogen-driven. In-depth studies are needed to understand the underlying immunologic mechanism(s). These encouraging results for a vaccine intended for use in pregnant women should be confirmed in higher animals.
Highlights
Pregnant women from developing countries are at high-risk of hepatitis E-associated high mortality and constitute priority population for vaccination
With the identification of a neutralization epitope (NE, nt458-607, 150aa) within Open Reading Frame-2 (ORF-2) in 2004 [16], we evaluated the utility of this smaller region in vaccine development
The results clearly show that even a single dose of the vaccine could induce 100% seroconversion and high anti-Hepatitis E virus (HEV) titres in both balb/c and C57BL/6 mice, irrespective of pregnancy
Summary
Pregnant women from developing countries are at high-risk of hepatitis E-associated high mortality and constitute priority population for vaccination. Of the two vaccine candidates completing clinical trials, one was a 56 kDa protein produced in insect cells which showed 95.5% efficacy after administration of three doses of 20 μg each at 0, 1 and 6 months [13]. The other was a bacterially expressed protein HEV239, which showed 100% efficacy on administration of three doses of 30 μg each at 0, 1 and 6 months [12]. This vaccine, Hecolin® is commercially available for use in China, but not globally, so far. Cross-protective efficacy was evident as the predominant strain in the area was genotype-4 while the vaccine was derived from genotype-1 virus
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