Schistosoma mansoni infection alters the host pre-vaccination environment resulting in blunted Hepatitis B vaccination immune responses

Schistosomiasis is a disease caused by parasitic flatworms of the Schistosoma spp., and is increasingly recognized to alter the immune system, and the potential to respond to vaccines. The impact of endemic infections on protective immunity is critical to inform vaccination strategies globally. We assessed the influence of Schistosoma mansoni worm burden on multiple host vaccine-related immune parameters in a Ugandan fishing cohort (n = 75) given three doses of a Hepatitis B (HepB) vaccine at baseline and multiple timepoints post-vaccination. We observed distinct differences in immune responses in instances of higher worm burden, compared to low worm burden or non-infected. Concentrations of pre-vaccination serum schistosome-specific circulating anodic antigen (CAA), linked to worm burden, showed a significant bimodal distribution associated with HepB titers, which was lower in individuals with higher CAA values at month 7 post-vaccination (M7). Comparative chemokine/cytokine responses revealed significant upregulation of CCL19, CXCL9 and CCL17 known to be involved in T cell activation and recruitment, in higher CAA individuals, and CCL17 correlated negatively with HepB titers at month 12 post-vaccination. We show that HepB-specific CD4(+) T cell memory responses correlated positively with HepB titers at M7. We further established that those participants with high CAA had significantly lower frequencies of circulating T follicular helper (cTfh) subpopulations pre- and post-vaccination, but higher regulatory T cells (Tregs) post-vaccination, suggesting changes in the immune microenvironment in high CAA could favor Treg recruitment and activation. Additionally, we found that changes in the levels of innate-related cytokines/chemokines CXCL10, IL-1 & beta;, and CCL26, involved in driving T helper responses, were associated with increasing CAA concentration. This study provides further insight on pre-vaccination host responses to Schistosoma worm burden which will support our understanding of vaccine responses altered by pathogenic host immune mechanisms and memory function and explain abrogated vaccine responses in communities with endemic infections.Author summarySchistosomiasis drives host immune responses for optimal pathogen survival, potentially altering host responses to vaccine-related antigen. Chronic schistosomiasis and co-infection with hepatotropic viruses are common in countries where schistosomiasis is endemic. We explored the impact of Schistosoma mansoni (S. mansoni) worm burden on Hepatitis B (HepB) vaccination of individuals from a fishing community in Uganda. We demonstrate that higher schistosome-specific antigen (circulating anodic antigen, CAA) concentration pre-vaccination, is associated with lower HepB antibody titers post-vaccination at month 7. We show higher pre-vaccination levels of CCL17 in instances of high CAA that negatively associate with HepB antibody titers month 12 post-vaccination and coincided with lower frequencies of circulating T follicular helper cell populations (cTfh), proliferating antibody secreting cells (ASCs), and higher frequencies of regulatory T cells (Tregs). We also show that monocyte function is important in HepB vaccine responses, and high CAA is associated with alterations in the early innate cytokine/chemokine microenvironment. Our findings suggest that in individuals with high CAA and likely high worm burden, schistosomiasis can create an environment that is polarized against optimal host immune responses to the vaccine, which puts many endemic communities at risk for infection against HepB and other diseases that are preventable by vaccines.Cancer Signaling networks and Molecular Therapeutic

Characterization of Foot-And-Mouth Disease Viruses (FMDVs) from Ugandan Cattle Outbreaks during 2012-2013: Evidence for Circulation of Multiple Serotypes

<div><p>To investigate the foot-and-mouth disease virus (FMDV) serotypes circulating in Uganda’s cattle population, both serological and virological analyses of samples from outbreaks that occurred during 2012–2013 were performed. Altogether, 79 sera and 60 oropharyngeal fluid (OP)/tissue/oral swab samples were collected from herds with reported FMD outbreaks in seven different Ugandan districts. Overall, 61/79 (77%) of the cattle sera were positive for antibodies against FMDV by PrioCHECK FMDV NS ELISA and solid phase blocking ELISA detected titres ≥ 80 for serotypes O, SAT 1, SAT 2 and SAT 3 in 41, 45, 30 and 45 of these 61 seropositive samples, respectively. Virus neutralisation tests detected the highest levels of neutralising antibodies (titres ≥ 45) against serotype O in the herds from Kween and Rakai districts, against SAT 1 in the herd from Nwoya district and against SAT 2 in the herds from Kiruhura, Isingiro and Ntungamo districts. The isolation of a SAT 2 FMDV from Isingiro was consistent with the detection of high levels of neutralising antibodies against SAT 2; sequencing (for the VP1 coding region) indicated that this virus belonged to lineage I within this serotype, like the currently used vaccine strain. From the Wakiso district 11 tissue/swab samples were collected; serotype A FMDV, genotype Africa (G-I), was isolated from the epithelial samples. This study shows that within a period of less than one year, FMD outbreaks in Uganda were caused by four different serotypes namely O, A, SAT 1 and SAT 2. Therefore, to enhance the control of FMD in Uganda, there is need for efficient and timely determination of outbreak virus strains/serotypes and vaccine matching. The value of incorporating serotype A antigen into the imported vaccines along with the current serotype O, SAT 1 and SAT 2 strains should be considered.</p></div

Neighbor-joining phylogeny tree based on serotype SAT 2 FMDV VP1 coding sequences.

<p>The relationships between the Ugandan 2013 SAT 2 FMD viruses and selected East African SAT 2 viruses are shown. The five 2013 Ugandan and one 2012 Kenyan outbreak FMDV (K125/12) sequences are marked with asterisks (*), while the strain K52/84** is the SAT 2 FMD virus strain incorporated in the trivalent vaccine (O, SAT 1 and SAT 2) as used in Uganda.</p

Summary of antibody analysis by PrioCHECK FMDV NS ELISA, SPBE antibody ELISAs and VNTs.

<p>^a: one herd was sampled in each district</p><p>^b: samples with titres ≥ 80 were considered positive (all anti-NSP positive samples were tested in all SPBEs).</p><p>^c: samples with titre >45 were considered positive.</p><p>^d: sera collected during 2012 outbreaks</p><p>^e: sera collected during 2013 outbreaks</p><p>^f: the two samples positive in SAT 1-VNT had higher titres in SAT 2-VNT (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0114811#pone.0114811.s001" target="_blank">S1 Table</a>)</p><p>na: not applicable because all samples were negative in the SPBE</p><p>nd: not done</p><p>Summary of antibody analysis by PrioCHECK FMDV NS ELISA, SPBE antibody ELISAs and VNTs.</p

Alignment of serotype A FMDV VP1 amino acid sequences.

<p>The VP1 amino acid sequences were inferred from one of the Ugandan 2013 serotype A FMDV nucleotide sequences (marked with an asterisk (*)) and selected African serotype A FMDV strains. The dots indicate identity with the vaccine strain sequence (K5/1980**) that is the reference sequence.</p

Eastern Africa serotype A and SAT 2 FMDV sequences used for comparisons in this study.

<p>*: 2012–2013 Ugandan and one 2012 Kenyan outbreak FMDV sequences included in this study</p><p>**: vaccine strain sequences</p><p>N/A: means not available.</p><p>Eastern Africa serotype A and SAT 2 FMDV sequences used for comparisons in this study.</p

Alignment of serotype SAT 2 FMDV VP1 amino acid sequences.

<p>The VP1 amino acid sequences were inferred from one of the 2013 outbreak nucleotide sequences (marked with an asterisk (*)) and earlier SAT 2 FMDV strains. Identities with the reference vaccine strain sequence (K52/84**) are indicated by dots. Similar amino acid variation exists between the reference sequence and the Ugandan 2013 isolates and a Kenyan outbreak isolate (K125/12*) sequence (unpublished data).</p