Oral vaccines, whether living or non-living, viral or bacterial, elicit diminished immune responses or have lower efficacy in developing countries than in developed countries. Here I describe studies ...with a live oral cholera vaccine that include older children no longer deriving immune support from breast milk or maternal antibodies and that identify some of the factors accounting for the lower immunogenicity, as well as suggesting counter-measures that may enhance the effectiveness of oral immunization in developing countries. The fundamental breakthrough is likely to require reversing effects of the 'environmental enteropathy' that is often present in children living in fecally contaminated, impoverished environments.
We performed a systematic literature review and meta-analysis examining the association between diarrhea in young children in nonindustrialized settings and Giardia lamblia infection. Eligible were ...case/control and longitudinal studies that defined the outcome as acute or persistent (>14 days) diarrhea, adjusted for confounders and lasting for at least 1 year. Data on G. lamblia detection (mainly in stools) from diarrhea patients and controls without diarrhea were abstracted. Random effects model meta-analysis obtained pooled odds ratios (ORs) and 95% confidence intervals (CIs). Twelve nonindustrialized-setting acute pediatric diarrhea studies met the meta-analysis inclusion criteria. Random-effects model meta-analysis of combined results (9774 acute diarrhea cases and 8766 controls) yielded a pooled OR of 0.60 (95% CI, .38-.94; P = .03), indicating that G. lamblia was not associated with acute diarrhea. However, limited data suggest that initial Giardia infections in early infancy may be positively associated with diarrhea. Meta-analysis of 5 persistent diarrhea studies showed a pooled OR of 3.18 (95% CI, 1.50-6.76; P < .001), positively linking Giardia with that syndrome. The well-powered Global Enteric Multicenter Study (GEMS) is prospectively addressing the association between G. lamblia infection and diarrhea in children in developing countries.
Klemm et al. (mBio 9:e00105-18, 2018, https://doi.org/10.1128/mBio.00105-18) present comprehensive antibiotic sensitivity patterns and genomic sequence data on
serovar Typhi blood culture isolates ...from typhoid fever cases during an epidemic in Pakistan. Microbiologic and genomic data pinpoint the identities and locations of the antimicrobial resistance genes and the outbreak strain's lineage. They propose that
serovar Typhi be added to the list of bacterial pathogens of public health importance that have become extensively drug resistant (XDR). This paper portends possible dire scenarios for typhoid fever control if XDR strains disseminate globally. Since the outbreak strain is of the H58 haplotype, known for its ability to spread worldwide and displace endemic
Typhi, this concern is well-founded. The report of Klemm et al. forewarns the global community to address control of typhoid fever more aggressively through prevention, should therapeutic options disappear. This Commentary frames the Klemm et al. findings within a historic perspective.
Summary Background A recombinant, replication-competent vesicular stomatitis virus-based vaccine expressing a surface glycoprotein of Zaire Ebolavirus (rVSV-ZEBOV) is a promising Ebola vaccine ...candidate. We report the results of an interim analysis of a trial of rVSV-ZEBOV in Guinea, west Africa. Methods For this open-label, cluster-randomised ring vaccination trial, suspected cases of Ebola virus disease in Basse-Guinée (Guinea, west Africa) were independently ascertained by Ebola response teams as part of a national surveillance system. After laboratory confirmation of a new case, clusters of all contacts and contacts of contacts were defined and randomly allocated 1:1 to immediate vaccination or delayed (21 days later) vaccination with rVSV-ZEBOV (one dose of 2 × 107 plaque-forming units, administered intramuscularly in the deltoid muscle). Adults (age ≥18 years) who were not pregnant or breastfeeding were eligible for vaccination. Block randomisation was used, with randomly varying blocks, stratified by location (urban vs rural) and size of rings (≤20 vs >20 individuals). The study is open label and masking of participants and field teams to the time of vaccination is not possible, but Ebola response teams and laboratory workers were unaware of allocation to immediate or delayed vaccination. Taking into account the incubation period of the virus of about 10 days, the prespecified primary outcome was laboratory-confirmed Ebola virus disease with onset of symptoms at least 10 days after randomisation. The primary analysis was per protocol and compared the incidence of Ebola virus disease in eligible and vaccinated individuals in immediate vaccination clusters with the incidence in eligible individuals in delayed vaccination clusters. This trial is registered with the Pan African Clinical Trials Registry, number PACTR201503001057193. Findings Between April 1, 2015, and July 20, 2015, 90 clusters, with a total population of 7651 people were included in the planned interim analysis. 48 of these clusters (4123 people) were randomly assigned to immediate vaccination with rVSV-ZEBOV, and 42 clusters (3528 people) were randomly assigned to delayed vaccination with rVSV-ZEBOV. In the immediate vaccination group, there were no cases of Ebola virus disease with symptom onset at least 10 days after randomisation, whereas in the delayed vaccination group there were 16 cases of Ebola virus disease from seven clusters, showing a vaccine efficacy of 100% (95% CI 74·7–100·0; p=0·0036). No new cases of Ebola virus disease were diagnosed in vaccinees from the immediate or delayed groups from 6 days post-vaccination. At the cluster level, with the inclusion of all eligible adults, vaccine effectiveness was 75·1% (95% CI −7·1 to 94·2; p=0·1791), and 76·3% (95% CI −15·5 to 95·1; p=0·3351) with the inclusion of everyone (eligible or not eligible for vaccination). 43 serious adverse events were reported; one serious adverse event was judged to be causally related to vaccination (a febrile episode in a vaccinated participant, which resolved without sequelae). Assessment of serious adverse events is ongoing. Interpretation The results of this interim analysis indicate that rVSV-ZEBOV might be highly efficacious and safe in preventing Ebola virus disease, and is most likely effective at the population level when delivered during an Ebola virus disease outbreak via a ring vaccination strategy. Funding WHO , with support from the Wellcome Trust (UK) ; Médecins Sans Frontières ; the Norwegian Ministry of Foreign Affairs through the Research Council of Norway; and the Canadian Government through the Public Health Agency of Canada, Canadian Institutes of Health Research , International Development Research Centre , and Department of Foreign Affairs, Trade and Development.
The “Moore swab” is a classic environmental surveillance tool whereby a gauze pad tied with string is suspended in flowing water or wastewater contaminated with human feces and harboring enteric ...pathogens that pose a human health threat. In contrast to single volume “grab” samples, Moore swabs act as continuous filters to “trap” microorganisms, which are subsequently isolated and confirmed using appropriate laboratory methods. Continuous filtration is valuable for the isolation of transiently present pathogens such as human-restricted
Salmonella enterica
serovars Typhi and Paratyphi A and B.
ABSTRACT
The “Moore swab” is a classic environmental surveillance tool whereby a gauze pad tied with string is suspended in flowing water or wastewater contaminated with human feces and harboring enteric pathogens that pose a human health threat. In contrast to single volume “grab” samples, Moore swabs act as continuous filters to “trap” microorganisms, which are subsequently isolated and confirmed using appropriate laboratory methods. Continuous filtration is valuable for the isolation of transiently present pathogens such as human-restricted
Salmonella enterica
serovars Typhi and Paratyphi A and B. The technique was first proposed (1948) to trace
Salmonella
Paratyphi B systematically through sewers to pinpoint the residence of a chronic carrier responsible for sporadic outbreaks of paratyphoid fever. From 1948 to 1986, Moore swabs proved instrumental to identify long-term human reservoirs (chronic carriers) and long-cycle environmental transmission pathways of
S
. Typhi and Paratyphi, for example, to decipher endemic transmission in Santiago, Chile, during the 1980s. Despite limitations such as intermittent shedding of typhoidal
Salmonella
by humans and the effects of dilution,
S
. Typhi and
S
. Paratyphi have been recovered from sewers, surface waters, irrigation canals, storm drains, flush toilets, and septic tanks by using Moore swabs. Driven by the emergence of multiple antibiotic-resistant
S
. Typhi and
S
. Paratyphi A strains that limit treatment options, several countries are embarking on accelerated typhoid control programs using vaccines and environmental interventions. Moore swabs, which are regaining appreciation as important components of the public health/environmental microbiology toolbox, can enhance environmental surveillance for typhoidal
Salmonella
, thereby contributing to the control of typhoid fever.
Background. Enteric fever caused by Salmonella Typhi remains a major public health problem in developing countries. Typbar-TCV is a single-dose typhoid Vi polysaccharide-tetanus toxoid conjugate ...vaccine for persons ≥6 months of age. Methods. Six hundred fifty-four healthy subjects aged 2–45 years enrolled in a double-blind, randomized controlled trial (RCT) received a single dose of Typbar-TCV or comparator "Vi polysaccharide" (Typbar), and 327 healthy subjects aged 6–23 months received a single dose of Typbar-TCV in an open-label trial (OLT); both received single- or multidose presentations from different lots. After 2 years, subsets in each group received a booster dose. The primary objective included analysis of geometric mean titer (GMTs) and 4-fold rise of anti-Vi serum immunoglobulin G (IgG) enzyme-linked immunosorbent assay titers over baseline (seroconversion SCN) 42 days after immunization. Results. Typbar-TCV recipients in the RCT attained higher anti-Vi IgG GMTs 42 days after immunization (SCN, 97%; GMT, 1293 95% confidence interval {CI}, 1153–1449) than recipients of (SCN, 93%; GMT, 411 95% CI, 359–471) (P<.001). Typbar-TCV was highly immunogenic in the OLT (SCN, 98%; GMT, 1937 95% CI, 1785–2103). Two years after vaccination, anti-Vi titers remained higher in Typbar-TCV subjects (GMT, 82 95% CI, 73–92); and exhibited higher avidity (geometric mean avidity index GMAI, 60%) than in Typbar recipients (GMT, 46 95% CI, 40–53; GMAI 46%) in the RCT (P < .001). OLT Typbar-TCV recipients achieved GMT of 48 (95% CI, 42–55) and GMAI of 57%. Typbar-TCV induced multiple IgG subclasses and strong booster responses in all ages. No serious vaccine-attributable adverse events were observed. Conclusions. Single-dose Typbar-TCV is well tolerated and induces robust and long-lasting serum anti-Vi IgG across age groups. Clinical Trials Registration. CTRI/2011/08/001957, CTRI/2014/01/004341.
Typhoid fever caused by infection with Salmonella enterica subspecies enterica serotype Typhi (S. Typhi), an important public health problem in many low- and middle-income countries, is transmitted ...by ingestion of water or food contaminated by feces or urine from individuals with acute or chronic S. Typhi infection. Most chronic S. Typhi carriers (shedding for ≥12 months) harbor infection in their gallbladder wherein preexisting pathologies, particularly cholelithiasis, provide an environment that fosters persistence. Much less appreciated is the existence of non-gallbladder hepatobiliary chronic S. Typhi carriers and urinary carriers. The former includes parasitic liver flukes as a chronic carriage risk factor. Chronic urinary carriers typically have pathology of their urinary tract, with or without renal or bladder stones. Even as the prevalence of multidrug-resistant and extensively drug-resistant S. Typhi strains is rising, global implementation of highly effective typhoid vaccines is increasing. There is also renewed interest in identifying, monitoring, and (where possible) treating chronic carriers who comprise the long-term reservoir of S. Typhi.
Summary Background Despite the heightened risk of serious influenza during infancy, vaccination is not recommended in infants younger than 6 months. We aimed to assess the safety, immunogenicity, and ...efficacy of maternal immunisation with trivalent inactivated influenza vaccine for protection of infants against a first episode of laboratory-confirmed influenza. Methods We did this prospective, active-controlled, observer-blind, randomised phase 4 trial at six referral centres and community health centres in Bamako, Mali. Third-trimester pregnant women (≥28 weeks' gestation) were randomly assigned (1:1), via a computer-generated, centre-specific list with alternate block sizes of six or 12, to receive either trivalent inactivated influenza vaccine or quadrivalent meningococcal vaccine. Study personnel administering vaccines were not masked to treatment allocation, but allocation was concealed from clinicians, laboratory personnel, and participants. Infants were visited weekly until age 6 months to detect influenza-like illness; laboratory-confirmed influenza diagnosed with RT-PCR. We assessed two coprimary objectives: vaccine efficacy against laboratory-confirmed influenza in infants born to women immunised any time prepartum (intention-to-treat population), and vaccine efficacy in infants born to women immunised at least 14 days prepartum (per-protocol population). The primary outcome was the occurrence of a first case of laboratory-confirmed influenza by age 6 months. This trial is registered with ClinicalTrials.gov , number NCT01430689. Findings We did this trial from Sept 12, 2011, to Jan 28, 2014. Between Sept 12, 2011, and April 18, 2013, we randomly assigned 4193 women to receive trivalent inactivated influenza vaccine (n=2108) or quadrivalent meningococcal vaccine (n=2085). There were 4105 livebirths; 1797 (87%) of 2064 infants in the trivalent inactivated influenza vaccine group and 1793 (88%) of 2041 infants in the quadrivalent meningococcal vaccine group were followed up until age 6 months. We recorded 5279 influenza-like illness episodes in 2789 (68%) infants, of which 131 (2%) episodes were laboratory-confirmed influenza. 129 (98%) cases of laboratory-confirmed influenza were first episodes (n=77 in the quadrivalent meningococcal vaccine group vs n=52 in the trivalent inactivated influenza vaccine group). In the intention-to-treat population, overall infant vaccine efficacy was 33·1% (95% CI 3·7–53·9); in the per-protocol population, vaccine efficacy was 37·3% (7·6–57·8). Vaccine efficacy remained robust during the first 4 months of follow-up (67·9% 95% CI 35·1–85·3 by intention to treat and 70·2% 35·7–87·6 by per protocol), before diminishing during the fifth month (57·3% 30·6–74·4 and 60·7 33·8–77·5, respectively). Adverse event rates in women and infants were similar among groups. Pain at the injection site was more common in women given quadrivalent meningococcal vaccine than in those given trivalent inactivated influenza vaccine (n=253 vs n=132; p<0·0001), although 354 92% reactions were mild. Obstetrical and non-obstetrical serious adverse events were reported in 60 (3%) women in the quadrivalent meningococcal vaccine group and 61 (3%) women in the trivalent inactivated influenza vaccine group. Presumed neonatal infection was more common in infants in the trivalent inactivated influenza vaccine group than in those in the quadrivalent meningococcal vaccine group (n=60 vs n=37; p=0·02). No serious adverse events were related to vaccination. Interpretation Vaccination of pregnant women with trivalent inactivated influenza vaccine in Mali—a poorly resourced country with high infant mortality—was technically and logistically feasible and protected infants from laboratory-confirmed influenza for 4 months. With adequate financing to procure the vaccine, implementation will parallel the access to antenatal care and immunisation coverage of pregnant women with tetanus toxoid. Funding Bill & Melinda Gates Foundation.
The interruption of malaria transmission worldwide is one of the greatest challenges for international health and development communities. The current expert view suggests that, by aggressively ...scaling up control with currently available tools and strategies, much greater gains could be achieved against malaria, including elimination from a number of countries and regions; however, even with maximal effort we will fall short of global eradication. The Malaria Eradication Research Agenda (malERA) complements the current research agenda--primarily directed towards reducing morbidity and mortality--with one that aims to identify key knowledge gaps and define the strategies and tools that will result in reducing the basic reproduction rate to less than 1, with the ultimate aim of eradication of the parasite from the human population. Sustained commitment from local communities, civil society, policy leaders, and the scientific community, together with a massive effort to build a strong base of researchers from the endemic areas will be critical factors in the success of this new agenda.
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