Daniel E. Velasquez

Multiple Norovirus Infections in a Birth Cohort in a Peruvian Periurban Community

Serial norovirus infections with multiple genotypes were found among a Peruvian birth cohort early in infancy. Protection against the subsequent infection was genotype specific, suggesting that norovirus vaccines may need to target multiple genotypes.

Interference of Monovalent, Bivalent, and Trivalent Oral Poliovirus Vaccines on Monovalent Rotavirus Vaccine Immunogenicity in Rural Bangladesh

BACKGROUND Trivalent oral poliovirus vaccine (OPV) is known to interfere with monovalent rotavirus vaccine (RV1) immunogenicity. The interference caused by bivalent and monovalent OPV formulations, which will be increasingly used globally in coming years, has not been examined. We conducted a post hoc analysis to assess the effect of coadministration of different OPV formulations on RV1 immunogenicity. METHODS Healthy infants in Matlab, Bangladesh, were randomized to receive 3 doses of monovalent OPV type 1 or bivalent OPV types 1 and 3 at either 6, 8, and 10 or 6, 10, and 14 weeks of age or trivalent OPV at 6, 10, and 14 weeks of age. All infants received 2 doses of RV1 at about 6 and 10 weeks of age. Concomitant administration was defined as RV1 and OPV given on the same day; staggered administration as RV1 and OPV given ≥1 day apart. Rotavirus seroconversion was defined as a 4-fold rise in immunoglobulin A titer from before the first RV1 dose to ≥3 weeks after the second RV1 dose. RESULTS There were no significant differences in baseline RV1 immunogenicity among the 409 infants included in the final analysis. Infants who received RV1 and OPV concomitantly, regardless of OPV formulation, were less likely to seroconvert (47%; 95% confidence interval, 39%-54%) than those who received both vaccines staggered ≥1 day (63%; 57%-70%; P < .001). For staggered administration, we found no evidence that the interval between RV1 and OPV administration affected RV1 immunogenicity. CONCLUSIONS Coadministration of monovalent, bivalent, or trivalent OPV seems to lower RV1 immunogenicity. CLINICAL TRIALS REGISTRATION NCT01633216.

Strain diversity plays no major role in the varying efficacy of rotavirus vaccines: an overview.

While a monovalent Rotarix® [RV1] and a pentavalent RotaTeq® [RV5] have been extensively tested and found generally safe and equally efficacious in clinical trials, the question still lingers about the evolving diversity of circulating rotavirus strains over time and their relationship with protective immunity induced by rotavirus vaccines. We reviewed data from clinical trials and observational studies that assessed the efficacy or field effectiveness of rotavirus vaccines against different rotavirus strains worldwide. RV1 provided broad clinical efficacy and field effectiveness against severe diarrhea due to all major circulating strains, including the homotypic G1P[8] and the fully heterotypic G2P[4] strains. Similarly, RV5 provided broad efficacy and effectiveness against RV5 and non-RV5 strains throughout different locations. Rotavirus vaccination provides broad heterotypic protection; however continuing surveillance is needed to track the change of circulating strains and monitor the effectiveness and safety of vaccines.

Association of Maternal Immunity with Rotavirus Vaccine Immunogenicity in Zambian Infants.

Introduction Live attenuated oral vaccines against rotavirus (RV) have been shown to be less efficacious in children from developing countries. Reasons for this disparity are not fully understood. We assessed the role of maternal factors including breast milk RV-specific IgA, transplacentally acquired infant serum RV-specific IgG and maternal HIV status in seroconversion among Zambian infants routinely immunized with Rotarix™ (RV1). Methods 420 mother-child pairs were recruited at infant age 6–12 weeks in Lusaka. Clinical information and samples were collected at baseline and at one month following the second dose of RV1. Determination of breast milk RV-specific IgA and serum RV-specific IgA and IgG was done using standardized ELISA. Seroconversion was defined as a ≥ 4 fold rise in serum IgA titre from baseline to one-month post RV1 dose 2, while seropositivity of IgA was defined as serum titre ≥ 40 and antibody variables were modelled on log-base 2. Logistic regression was used to identify predictors of the odds of seroconversion. Results Baseline infant seropositivity was 25.5% (91/357). The seroconversion frequency was 60.2% (130/216). Infants who were IgA seropositive at baseline were less likely to seroconvert compared to their seronegative counterparts (P = 0.04). There was no evidence of an association between maternal HIV status and seroconversion (P = 0.25). Higher titres of breast milk rotavirus-specific IgA were associated with a lower frequency of seroconverson (Nonparametric test for trend Z = -2.84; P<0.01): a two-fold increase in breast milk RV-specific IgA titres was associated with a 22% lower odds of seroconversion (OR = 0.80; 95% CI = 0.68–0.94; P = 0.01). There was seasonal variation in baseline breast milk rotavirus-specific IgA titres, with significantly higher GMTs during the cold dry months (P = 0.01). Conclusion Low immunogenicity of RV1 vaccine could be explained in part by exposure to high antibody titres in breast milk and early exposure to wild-type rotavirus infections. Potential interference of anti-RV specific IgA in breast milk and pre-vaccination serum RV specific-IgA and IgG titres with RV1 seroconversion and effectiveness requires further research.

Rotavirus-specific IgG antibodies from mothers' serum may inhibit infant immune responses to the pentavalent rotavirus vaccine.

© 2014 Lippincott Williams & Wilkins www.pidj.com | 115 Rotavirus-specific IgG Antibodies From Mothers’ Serum May Inhibit Infant Immune Responses to the Pentavalent Rotavirus Vaccine in Exon 2 of the IL2RG gene (c.252C>A, p.Asn84Lys; MIM# 300400) and curative therapy with stem cell transplantation was initiated at our specialized medical center. We identified rotavirus vaccine strain in stool samples by sequencing of 8 different gene segments (VP1, VP2, VP4, VP6, VP7, NSP2, NSP4 and NSP5). In all segments vaccine-associated sequences harboring few new mutations were found, leading to the conclusion that the child’s chronic gastroenteritis was caused by persisting infection with the vaccine rotavirus strain (see Table, Supplemental Digital Content 1, http://links.lww.com/INF/B978). No other pathogen could be identified in multiple stool samples, including uncommon parasites, coccidia and helminths. Notably, all stool, blood and respiratory specimens were also tested by Luminex xTAG respiratory and xTAG gastrointestinal pathogen panel (Abbott Molecular, Wiesbaden, Germany). In samples from the respiratory tract, we detected high copy numbers of human bocavirus (HBoV) and rhinovirus, which most likely subsequently caused respiratory failure in our patient. Despite all intensive supportive care and treatment, the boy’s condition deteriorated and he died on day 1 after stem cell transplantation. In addition to the association with intussusception, shedding of rotavirus for a period of time after oral vaccination and vaccineinduced severe gastroenteritis including infection of healthy siblings have been reported. The observation of acute and chronic infections by vaccine strain rotavirus in immunocompromised children led to the addition of SCID as contraindication for administration of rotavirus vaccine. Our SCID patient presented already with advanced disease and severely reduced general condition. We believe that viral shedding of rotavirus for such a prolonged period of time has not been previously reported and might be explained by the lack of timely adequate medical management. We cannot completely exclude that other gastrointestinal infections and other comorbidities might have been involved, but we propose that vaccine-acquired rotavirus-infection had probably contributed significantly to the fatal outcome. The clinical manifestation and diagnosis of SCID patients might be delayed well into the life period after the recommended vaccination schedule. Therefore, we emphasize the negative effect that rotavirus vaccination might have in these endangered patients and we strongly support efforts of mandatory newborn screening for SCID.

Cavia porcellus as a Model for Experimental Infection by Trypanosoma cruzi

The guinea pig (Cavia porcellus) is a natural reservoir for Trypanosoma cruzi but has seldom been used as an experimental infection model. We developed a guinea pig infection model for acute and chronic Chagas disease. Seventy-two guinea pigs were inoculated intradermally with 10(4) trypomastigotes of T. cruzi strain Y (experimental group); 18 guinea pigs were used as control group. Eight animals from the experimental group and two from the control group were sacrificed 5, 15, 20, 25, 40, 55, 115, 165, and 365 days after inoculation. During the acute phase (15 to 55 days), we observed parasitemia (with a peak on day 20) and positive IgM and IgG Western blots with anti-shed acute-phase antigen bands. The cardiac tissue showed vasculitis, necrosis (on days 40 to 55), moderate to severe inflammation, and abundant amastigote nests. Smaller numbers of amastigote nests were also present in kidney, brain, and other organs. In the early chronic phase (115 to 165 days), parasitemia disappeared and anti-T. cruzi IgG antibodies were still detectable. In cardiac tissue, the number of amastigote nests and the grade of inflammation decreased. In the chronic phase (365 days), the cardiac tissue showed vasculitis and fibrosis; detectable parasite DNA was associated with higher grades of inflammation. The experimental T. cruzi infection model in guinea pigs shows kinetics and pathologic changes similar to those of the human disease.

Skin Vaccination against Rotavirus Using Microneedles: Proof of Concept in Gnotobiotic Piglets.

Live-attenuated oral rotavirus (RV) vaccines have lower efficacy in low income countries, and additionally are associated with a rare but severe adverse event, intussusception. We have been pursuing the development of an inactivated rotavirus vaccine (IRV) using the human rotavirus strain CDC-9 (G1P[8]) through parenteral immunization and previously demonstrated dose sparing and enhanced immunogenicity of intradermal (ID) unadjuvanted IRV using a coated microneedle patch in comparison with intramuscular (IM) administration in mice. The aim of this study was to evaluate the immune response and protection against RV infection and diarrhea conferred by the administration of the ID unadjuvanted IRV using the microneedle device MicronJet600® in neonatal gnotobiotic (Gn) piglets challenged with virulent Wa G1P[8] human RV. Three doses of 5 μg IRV when administered intradermally and 5 μg IRV formulated with aluminum hydroxide [Al(OH)3] when administered intramuscularly induced comparable rotavirus-specific antibody titers of IgA, IgG, IgG avidity index and neutralizing activity in sera of neonatal piglets. Both IRV vaccination regimens protected against RV antigen shedding in stools, and reduced the cumulative diarrhea scores in the piglets. This study demonstrated that the ID and IM administrations of IRV are immunogenic and protective against RV-induced diarrhea in neonatal piglets. Our findings highlight the potential value of an adjuvant sparing effect of the IRV ID delivery route.

Breastfeeding linked to the reduction of both rotavirus shedding and IgA levels after Rotarix® immunization in Mexican infants

We examined potential risk factors on vaccine virus shedding and antibody seroresponse to human rotavirus vaccine (Rotarix) in Mexican infants. Two doses of Rotarix were administered to infants during the first two visits for their routine childhood immunization (∼8 and 15weeks of age) in Mexico City. Infants characteristics and socioeconomic indicators were obtained, including history of long-term feeding practices (exclusively/predominantly breastfed and exclusively/predominantly non-breastfed). Two serum specimens were collected, one during the second rotavirus vaccine visit and one 7weeks later. Stool specimens were collected between days 4-7 after each of the two rotavirus vaccine doses. Rotavirus IgA and IgG titers in serum were determined by enzyme immunoassays (EIA) and rotavirus shedding in stool was assessed by EIA and confirmed by RT-PCR. The overall rotavirus IgA geometric mean titers (GMT) increased significantly post dose 2 from post dose 1 [176 (95%CI: 113-273) to 335 (238-471); p=0.020). Infants who were exclusively/predominantly breastfed were less likely to shed vaccine virus in stool than those who were formula-fed (22% vs. 43%, p=0.016). Infants who were breastfed had lower rotavirus IgA titers than those who were formula-fed after dose 1 [GMT: 145 (84-250) vs. 267 (126-566) p=0.188] and dose 2 [236 (147-378) vs.578 (367-910), p=0.007]. Infants who shed vaccine virus post dose 1 had significantly higher serum IgA GMT than those who did not shed [425 (188-965) vs. 150 (84-266), p=0.038]. Breastfeeding was linked with the reduction of both stool vaccine shedding, and IgA seroresponse. The reduced rotavirus replication in the gut and shedding after dose 1 may explain in part the lower IgA response in serum.

Needs, Acceptability, and Value of Humanitarian Medical Assistance in Remote Peruvian Amazon Riverine Communities

Much debate exists regarding the need, acceptability, and value of humanitarian medical assistance. We conducted a cross-sectional study on 457 children under 5 years from four remote riverine communities in the Peruvian Amazon and collected anthropometric measures, blood samples (1-4 years), and stool samples. Focus groups and key informant interviews assessed perspectives regarding medical aid delivered by foreigners. The prevalence of stunting, anemia, and intestinal parasites was 20%, 37%, and 62%, respectively. Infection with multiple parasites, usually geohelminths, was detected in 41% of children. The prevalence of intestinal parasites both individual and polyparasitism increased with age. Participants from smaller communities less exposed to foreigners expressed lack of trust and fear of them. However, participants from all communities were positive about foreigners visiting to provide health support. Prevalent health needs such as parasitic infections and anemia may be addressed by short-term medical interventions. There is a perceived openness to and acceptability of medical assistance delivered by foreign personnel.

Inactivated human rotavirus vaccine induces heterotypic antibody response: Correction and development of IgG avidity assay

To improve lower efficacy among infants in low income countries and the safety (e.g., rare but severe intussusception) of live oral rotavirus vaccines, we have developed CDC-9 strain with G1P[8] specificity as a candidate inactivated rotavirus vaccine (IRV). This IRV of 3 doses elicits high titers of IgG, neutralizing activity to homotypic and heterotypic human strains and IgG avidity in guinea pigs, thus is a promising alternative to enhance global immunization against rotavirus in children.