Progress toward sustainable influenza vaccination in the Lao Peoples' Democratic Republic, 2012-2018.

Despite global recommendations for influenza vaccination of high-risk, target populations, few low and middle-income countries have national influenza vaccination programs. Between 2012 and 2017, Lao PDR planned and conducted a series of activities to develop its national influenza vaccine program as a part of its overall national immunization program. In this paper, we review the underlying strategic planning for this process, and outline the sequence of activities, research studies, partnerships, and policy decisions that were required to build Laos' influenza vaccine program. The successful development and sustainability of the program in Laos offers lessons for other low and middle-income countries interested in initiating or expanding influenza immunization.

Evaluating interest in an influenza A(H5N1) vaccine among laboratory workers who work with highly-pathogenic avian influenza viruses in the United States.

BACKGROUND: Highly pathogenic avian influenza A (HPAI) viruses found in poultry and wild birds occasionally infect humans and can cause serious disease. In 2014, the Advisory Committee on Immunization Practices (ACIP) reviewed data from one licensed ASO3-adjuvanted influenza A(H5N1) vaccine for consideration of use during inter-pandemic periods among persons with occupational exposure. To guide vaccine policy decisions, we conducted a survey of laboratory workers to assess demand for HPAI vaccination. METHODS: We designed an anonymous web survey (EpiInfo 7.0) to collect information on demographics, type of work and time spent with HPAI viruses, and interest in HPAI vaccination. Eligible participants were identified from 42 entities registered with United States Department of Agriculture's Agricultural Select Agent program in 2016 and emailed electronic surveys. Personnel with Biosafety Level 3 enhanced (BSL-3E) laboratory access were surveyed. Descriptive analysis was performed. RESULTS: Overall, 131 responses were received from 33 principal investigators, 26 research scientists, 24 technicians, 15 postdoctoral fellows, 6 students, and 27 others. The estimated response rate was 15% among the laboratory personnel of responding principal investigators. One hundred respondents reported working in a BSL-3E area where HPAI experiments occurred with a mean time of 5.1-11.7 h per week. Overall, 49% were interested in receiving an A(H5N1) vaccine. By role, interest was highest among students (80%) and among those who spent >50% of their time in a BSL-3E area (64%). Most (61%) of those who said they might be or were not interested in vaccine believed it would not provide additional protection to current safety practices. CONCLUSIONS: Half of responding laboratory workers was interested in receiving an influenza A(H5N1) vaccine. HPAI vaccination of laboratory workers at risk of occupational exposure could be used along with existing safety practices to protect this population.

Rotavirus epidemiology: the Asian Rotavirus Surveillance Network.

Availability of new rotavirus vaccines has highlighted the need to collect local disease and economic burden data to aid decision makers at global, regional and country level. The World Health Organization and the GAVI Alliance recommended that generic protocols be used and that regional surveillance networks be established to collect these data, thereby helping to fast-track the introduction of these new vaccines into developing countries. Nine countries and regions participated in the first phase of the Asian Rotavirus Surveillance Network (ARSN), which collected data over a 2-year period during 2001-2003. Overall 45% of diarrhoea admissions in the region were positive for rotavirus, which was higher than had been anticipated. Significant rotavirus strain diversity was noted during the surveillance period. Data collection for a second phase of the ARSN commenced in 2004 and included a greater proportion of poorer countries that would in future be eligible for funding support for rotavirus immunization from GAVI. Limited economic evaluations in Asia have demonstrated the potential for new rotavirus vaccines to be cost-effective but more local analyses are required. Despite the ARSN's comprehensive data from a mix of developed and developing countries, Asia has lagged the Americas in terms of the introduction of rotavirus vaccines into National Immunization Programmes (NIPs). Lack on rotavirus vaccine efficacy data in Asia, particularly in poorer populations, will have contributed to this delay. Thus ensuring that all global regions are simultaneously involved in the evaluation of new vaccines from the beginning and also encouraging more regional collaborations of Ministry of Health representatives could help to accelerate the introduction of new vaccines into NIPs.

Rotavirus disease in Uzbekistan: cost-effectiveness of a new vaccine.

We evaluated the cost-effectiveness of rotavirus vaccination in Uzbekistan from the healthcare system and societal perspectives. Disease burden was estimated using national statistics on hospitalizations and deaths, and international estimates of under-five mortality. Without vaccination, the risk for rotavirus hospitalization by age 5 is 10 per 1000 children. Rotavirus hospitalizations cost US$ 406,000 annually, of which US$ 360,000 (89%) is for medical expenses and US$ 46,000 (11%) is for non-medical and indirect costs. Rotavirus mortality rate at 0.7 per 1000 derived from national data was three-fold lower than the same rate calculated from international estimates of under-five mortality. Rotavirus vaccination could reduce hospitalizations and deaths by 91% and avert US$ 370,000 in hospitalization costs alone. Vaccination would be cost-effective with vaccine prices in a range of US$ 2-25 per child. However, the cost-effectiveness is greatly influenced by mortality, vaccine price and vaccine efficacy.

Epidemiology and strain characterization of rotavirus diarrhea in Malaysia.

OBJECTIVES: The objectives of the study were to describe the epidemiology and strain characterization of rotavirus (RV), to determine the proportion of hospitalizations for diarrhea attributable to RV among children under 5 years of age, and to estimate the disease burden of RV diarrhea in Malaysia. METHODS: All children 0-59 months of age admitted for acute gastroenteritis to Kuala Lumpur Hospital (KLH) or Hospital Umum Sarawak (HUS) were surveyed. The periods of surveillance were from February 1, 2001 to April 30, 2003 in KLH and April 1, 2001 to March 31, 2003 for HUS. RESULTS: The highest rate of RV-associated diarrhea was among children aged 6-17 months, accounting for 55% of RV-associated diarrhea. There was no seasonality observed in either hospital. P[8]G9 strains were predominant, accounting for 73% of all strains in both hospitals, 80% from KLH and 61% from HUS. There was no mortality. CONCLUSIONS: RV was responsible for 38% of hospitalizations for diarrhea. It was most common in the 6-17 months age group. There was no seasonality observed for RV-associated diarrhea. The most prevalent strain of RV was P[8]G9. The estimated incidence of RV-associated diarrhea was 27 per 10000 population under the age of 5 years per year.

[Rotavirus surveillance data from Kunming Children's Hospital, 1998 - 2001].

OBJECTIVE: To study the epidemiological status on rotavirus diarrhea in Kunming to improve the rotavirus vaccine immunization program. METHODS: A hospital-based sentinel surveillance program for rotavirus was set up among children less than 5 years old with acute diarrhea in Kunming Children's Hospital. Clinical information and fecal specimens were collected and rotavirus were detected by polyacrylamide gel electrophoresis (PAGE) and/or enzyme linked immunosorbent assay (ELISA). Positive specimens were further serotyped or genotyped by ELISA and/or RT-PCR. RESULTS: During the three years of surveillance, 466 specimens were collected. Rotavirus were detected on 246 (52.8%) specimens. 97% of the rotavirus diarrhea cases occurred among children less than 2 years old. There was a peak of admissions for rotavirus diarrhea cases between October and December which accounted for 48% of all the rotavirus hospitalizations each year. Among 204 specimens with G serotyping, the predominant strain was serotype G1 (47.5%) followed by G2 (17.6%), G3 (15.7%), G9 (4.9%) and G4 (1.0%). Mixed infection (2.5%) were rare and 22 specimens (10.8%) remained non-typeable. P genotyping showed P[4], P[8] and P[6] were the most common strains, accounting for 29.3%, 27.6% and 13.8% respectively. P[4]G2 was the most common strain which accounted for 34.1% (14/41) followed by P[8]G1 (29.3%) and P[6]G9 (12.2%). Another 7 uncommon P-G combinations were also identified. CONCLUSION: Rotavirus was the major cause of acute diarrhea in Kunming. An effective rotavirus vaccine for prevention and control of rotavirus diarrhea should be developed.

[Surveillance finding on rotavirus in Changchun children's hospital during July 1998-June 2001].

OBJECTIVE: To establish baseline patterns of rotavirus diarrhea and to describe its epidemiologic features in Changchun city, prior to rotavirus vaccine immunization. METHODS: Hospital-based surveillance was conducted among children under 5 years old with acute diarrhea in Changchun Children's Hospital. Fecal samples were determined to identify rotavirus by PAGE and/or ELISA. G serotypes of rotavirus were identified by ELISA and/or nested RT-PCR. P genotyping were carried out by RT-PCR. All data were computerized and analysed by "Generic Manual on Rotavirus Surveillance" set by CDC in the USA. RESULTS: In total, 2 343 diarrhea cases were screened and 1 211 fecal samples were collected. Rotavirus was detected in 31.0% among outpatients and 52.9% in inpatients. During the peak of the season (November through March), 58.6% of diarrhea was caused by rotavirus among inpatients. 95.0% of rotavirus diarrhea cases occurred among children aged < 2 years. The predominant strain was serotype G1 (82.4%), followed by G2 (5.0%), G3 (3.3%), G4 (0.9%). P genotyping showed that P[8] and P[4] were the most common ones. Nine different P-G combinations were identified, four strains (P[8]G1, P[4]G2, P[8]G3, and P[8]G4) commonly seen worldwide accounted for 75.6% of the total. Taken together with uncommon strains, including the novel types P[4]G4 and P[8]G2, it highlights the extraordinary diversity of rotaviruses circulating in China. CONCLUSION: Rotavirus is the major cause of severe child diarrhea in Changchun. Developing a rotavirus vaccine for prevention of severe disease and reduction of treatment costs seemed to be necessary.

[Epidemiological study of rotavirus diarrhea in Beijing, China - a hospital-based surveillance from 1998 - 2001].

OBJECTIVE: To provide information on epidemiology of rotavirus infection in Beijing, China. METHODS: An ongoing hospital-based surveillance was conducted among children < 5yr old with acute diarrhea according to WHO generic protocol (CID-98). During a 3-year study (Apr. 1998 to Mar. 2001), a total of 484 stool samples were collected from 1 457 patients, including 275 samples from 1 048 outpatients and 209 samples from 409 inpatients. RESULTS: The overall detection rate of rotavirus infection was 25.4%. Rotavirus was responsible for 27.3% of diarrhea inpatients on a yearly base, and 46.2% during rotavirus season. Two peaks of diarrhea were observed each year, one in the summer (June-Sep.) due to bacterial dysentery (16.7%) and another in fall winter (Oct.-Dec.) due to rotavirus infection (23.0%). The detection rate on rotavirus was the highest in age group of 6 - 11 months (38.2%), followed by 1 - 2 years old (28.5%). Ninety six point eight percentage of children were infected under 3 years of age. The number of deaths, possibly caused by rotavirus diarrhea were accounted for 40% of all diarrhea deaths and 11.1% of the total deaths. Serotyping of 123 rotavirus isolates showed that serotype G1 (55.3%) was predominant, followed by G2 (26.8%), G3 (9.8%), G4 (0.8%), and 10 isolates (8.1%) remained non-typeable. Mixed infections (0.8%) seemed to be rare. CONCLUSION: Rotavirus diarrhea was an important infectious disease among children in Beijing. Safe and effective rotavirus vaccines for the prevention of severe diarrheas and the reduction of treatment costs are of significant importance to China.

Safety and immunogenicity of tetravalent rhesus-based rotavirus vaccine in Bangladesh.

BACKGROUND: Rotavirus is the most common cause of severe gastroenteritis among children worldwide. OBJECTIVES: To compare the safety, immunogenicity and shedding patterns of rhesus rotavirus (RRV)-tetravalent vaccine vs. placebo among infants in rural Bangladesh. METHODS: A double blinded, placebo-controlled trial was conducted in which infants (n = 120) were randomly assigned to receive three doses of either vaccine or placebo administered at approximately 6, 10 and 14 weeks of age together with routine immunizations. Data on possible adverse effects of vaccinations were collected daily for 7 days after each dose. Stool samples were collected after each dose, and serum samples were obtained before the first and after the third vaccination. RESULTS: Fever (> or = 38 degrees C), as measured by study assistants, was noted more frequently among vaccinees (15%) than among placebo recipients (2%) during the 7 days after vaccination but was not reported more frequently by parents of vaccinees vs. placebo recipients. Overall 87% of vaccinees had an antibody response (measured by IgA or anti-RRV-neutralizing antibodies) after vaccination compared with 32% of placebo recipients. Rates of seroconversion were higher among subjects with lower levels of prevaccination antibodies and those who shed rotavirus after vaccination. Vaccine strain viruses were detected in stools from placebo vaccine recipients who had evidence of IgA seroconversion. CONCLUSIONS: In this population RRV-tetravalent vaccine was comparably immunogenic and safe as in trials conducted in developed countries, where this vaccine has been proved effective in preventing severe rotavirus diarrhea. These data support continued evaluation of rotavirus vaccines in developing countries.

Multistate outbreak of Norwalk-like virus gastroenteritis associated with a common caterer.

In February 2000, an outbreak of gastroenteritis occurred among employees of a car dealership in New York. The same meal was also supplied to 52 dealerships nationwide, and 13 states reported illness at dealerships where the banquet was served. A retrospective cohort study was conducted to identify risk factors associated with the illness. Stool samples were collected to detect Norwalk-like virus, and sera were drawn and tested for immunoglobulin A antibodies to the outbreak strain. By univariate analysis, illness was significantly associated with consumption of any of four salads served at the banquet (relative risk = 3.8, 95% confidence interval: 2.5, 5.6). Norwalk-like virus was detected by reverse transcription-polymerase chain reaction assay in 32 of 59 stool samples from eight states. Nucleotide sequences of a 213-base pair fragment from 16 stool specimens collected from cases in eight states were identical, confirming a common source outbreak. Two of 15 workers at caterer A had elevated immunoglobulin A titers to an antigenically related Norwalk-like virus strain. This study highlights the value of molecular techniques to complement classic epidemiologic methods in outbreak investigations and underscores the critical role of food handlers in the spread of foodborne disease associated with Norwalk-like virus.

Rotavirus vaccine and intussusception. Where do we go from here?

Since the discovery of rotavirus in 1973, vaccine technology has moved from the use of monovalent attenuated animal rotavirus strains to the development of multivalent human-animal reassortment vaccines. The first licensed vaccine, a rhesus-human tetravalent vaccine, was licensed in 1998. This vaccine was withdrawn from the market a year later when it was noted that administration of vaccine was associated with an increased risk of intussusception. The future of rotavirus vaccine is dependent on the reasons for this association that have yet to be discovered.

Cost of diarrhea-associated hospitalizations and outpatient visits in an insured population of young children in the United States.

OBJECTIVE: To assess the financial and clinical burden of diarrhea- and rotavirus-associated disease among a population of privately insured US children. METHODS: For the period 1993 through 1996, we analyzed medical claims data from a large, administrative database containing information on approximately 300,000 children <5 years of age to examine trends in, and costs associated, with hospitalizations and outpatient visits for diarrhea. RESULTS: An annual average of 1,186 diarrhea-associated hospitalizations (35 per 10,000 children <5 years) and 33 386 outpatient visits (943 per 10,000 children <5 years) were reported, accounting for 4% of all hospitalizations and 2% of all outpatient visits among children <5 years of age. Diarrhea-associated hospitalizations and outpatient visits showed a distinct winter-spring peak consistent with that of rotavirus infection. The excess of diarrhea-associated events occurring during the winter-spring peak accounted for an average of 50% of all diarrhea-associated hospitalizations and 18% of all diarrhea-associated outpatient visits. The median cost (in 1998 constant dollars) of a diarrhea-associated hospitalization was $2,307, and that for a rotavirus-associated hospitalization was $2,303. Median costs of diarrhea- and rotavirus-associated outpatient visits were $47 and $57, respectively. CONCLUSIONS: Diarrhea is an important cause of morbidity in this insured population of young children. The epidemiologic features of diarrhea-associated events suggest that rotavirus is an important contributor to the overall morbidity from diarrhea. These disease burden and cost estimates should provide useful information with which to assess the costs and benefits of future interventions for rotavirus-associated illness.

"Norwalk-like viruses". Public health consequences and outbreak management.

"Norwalk-like viruses" (NLVs) cause outbreaks of gastroenteritis and are spread frequently through contaminated food or water. Molecular diagnostics now enables detecting viruses in clinical and environmental specimens, linking of NLV strains causing outbreaks in multiple geographic locations, and tracing them to their sources in contaminated food or water. This report reviews recent advances in NLV detection and provides guidelines and recommendations for investigating NLV-related outbreaks, including specimen collection and disease prevention and control. This report also updates information provided in CDC's previously published, Viral Agents of Gastroenteritis: Public Health Importance and Outbreak Management (MMWR 1990;39 [No. RR-5]: 1-24). These CDC recommendations are intended for public health professionals who investigate outbreaks of acute gastroenteritis but could be useful in academic and research settings as well.

Molecular and serologic characterization of novel serotype G8 human rotavirus strains detected in Blantyre, Malawi.

During a 2-year study of diarrhea among children in Blantyre, Malawi, greater than 50% of rotavirus strains genotyped by using reverse transcription-polymerase chain reaction possessed previously unrecognized combinations of the neutralization proteins VP7 and VP4. Serotype G8 rotaviruses, which have been identified recently in several African countries, were found to possess P[4] or P[6] VP4 genotype specificity. Two of these short electropherotype rotaviruses were further investigated: these comprised a P[6], G8 representative strain (MW23) and a P[4], G8 representative strain (MW333). The VP7 gene sequences of both strains exhibited greatest homology to human and animal serotype G8 rotaviruses. Sequence analysis of the VP4 gene of MW23 indicated closest identity to the P2A[6], G9 strain US1205 from the United States. The VP4 gene of MW333 was most closely related to the P[4], G12 strain L26 isolated in the Philippines and the Australian P[4], G2 strain RV-5. The NSP4 gene sequences of both strains were classified in NSP4 genetic group I. RNA-RNA hybridization demonstrated that each of these two strains is related to the DS-1 genogroup of human rotaviruses. Subgroup analysis and virus neutralization confirmed complete antigenic characterization of MW23 as subgroup I, P2A[6], G8 and MW333 as subgroup I, P1B[4], G8. The similarity of the VP7 gene sequences of the prototype strains described in this report to bovine serotype G8 rotaviruses suggests that they may represent human/bovine reassortant viruses.

Surveillance of rotavirus strains in the United States: identification of unusual strains. The National Rotavirus Strain Surveillance System collaborating laboratories.

Rotavirus strains from 964 fecal specimens collected from children at 11 U.S. hospital laboratories from November 1997 to March 1998 and from samples collected at 12 laboratories from November 1998 to March 1999 were typed for G and P proteins. Serotype G1 was the predominant serotype in 1997-1998 (88%), followed by G2 (6.2%), G9 (3.3%), and G3 (1.5%). This pattern was similar to that seen in 1998-1999: G1 (79%), G2 (15%), G9 (3.0%), G4 (1.6%), and G3 (0.3%). Novel P[9] strains were identified in both seasons, and analysis of a 364-nucleotide fragment from gene segment 4 of one of the strains demonstrated 97.3% nucleotide identity with the prototype P3[9],G3 strain, AU1, isolated in Japan. This is the first report of a human AU1-like strain in the United States. These results reinforce our initial findings that serotype G9 persists in the United States but has not become a predominant strain and that the common serotypes G1 to G4 account for almost 90% of strains in circulation. Other uncommon strains exist in the United States but may have been overlooked before because of their low prevalence and the use of inadequate diagnostic tools.

The epidemiology of enteric caliciviruses from humans: a reassessment using new diagnostics.

In the United States, acute gastroenteritis is one of the most commonly noted illnesses on hospital discharge records and death certificates, yet few of these cases have an etiologic diagnosis. The application of new molecular diagnostic methods has shown caliciviruses (previously referred to as the Norwalk family of viruses or small round structured viruses) to be the most common cause of acute gastroenteritis (AGE) outbreaks in the United States, and they may emerge as a common cause of sporadic cases of AGE among both children and adults. Novel molecular methods have permitted outbreak strains to be traced back to their common source and have led to the first identification of virus in implicated vehicles of infection-water, shellfish, and foods contaminated both at their source and by food handlers. The broad application of these methods to routine diagnosis in hospitals and public health laboratories is advancing our appreciation of the full burden of calicivirus-associated diarrhea, and it is opening new avenues for its prevention and control.

Cold weather seasonality of gastroenteritis associated with Norwalk-like viruses.

Norwalk-like viruses (NLVs) are the most common cause of acute nonbacterial gastroenteritis in adults, but little is known about their seasonality. The lack of specific diagnostic tools impeded study of these viruses in the past, and surveys using electron microscopy often grouped NLVs with other unrelated viruses. A search of the scientific literature found eight surveys of gastroenteritis, which were conducted for at least 1 year, that specifically identified NLVs. Unpublished data from laboratories of 4 NLV researchers were also used. These surveys, which were conducted in eight countries, reported sporadic cases and outbreaks of NLV-associated gastroenteritis among all age groups. The monthly occurrence of these cases and outbreaks was plotted, and while transmission occurred year-round in most surveys, a cold weather peak was demonstrated in 11 of the 12 studies. This key epidemiologic feature of the viruses has important implications concerning their mode of transmission and for understanding the etiology of acute gastroenteritis in adults.

Rotavirus vaccines and vaccination in Latin America.

Worldwide, rotaviruses account for more than 125 million cases of infantile gastroenteritis and nearly 1 million deaths per year, mainly in developing countries. Rather than other control measures, vaccination is most likely to have a major impact on rotavirus disease incidence. The peak incidence of rotavirus diarrhea occurs between 6 and 24 months of age. In developing countries, however, cases are not uncommon among children younger than 6 months. G serotypes 1 to 4 are responsible for most disease, but there are indications that in Brazil that G type 5 is of emerging epidemiological importance. Both homotypic and heterotypic responses are elicited during natural rotavirus infection, and the immunological response at the intestinal mucosal surface is probably the more consistent predictor of clinical immunity. With the primary objective of protecting children against life-threatening dehydrating diarrhea, many approaches to rotavirus vaccine development have been attempted. One vaccine, the tetravalent rhesus-human reassortant rotavirus vaccine (RRV-TV), was given licensing approval in the United States of America, introduced to the market, and later withdrawn. A number of studies have found better efficacy of RRV-TV in developed countries than in developing ones. Field trials with a 4 x 10(4) plaque-forming units (PFU) preparation of RRV-TV have been carried out in two countries in Latin America, Brazil and Peru. Those trials yielded protective efficacy rates against all rotavirus diarrhea ranging from 18% to 35%. Data from a large catchment trial in Venezuela with a higher RRV-TV dose, of 4 x 10(5) PFU/dose, indicated an efficacy rate of 48% against all rotavirus diarrhea and 88% against severe rotavirus diarrhea. It appears that breast-feeding does not compromise the efficacy of RRV-TV if three doses of the vaccine are administered. Similarly, possible interference of oral poliovirus vaccine with the "take" of the rotavirus vaccine can be overcome by giving three doses of the rotavirus vaccine or by using a higher-titer formulation of it. Wild enteroviruses, however, may cause primary rotavirus vaccine failure in developing countries. Studies in Peru with RRV-TV have shown a trend towards higher vaccine efficacy rates against "pure" (rotavirus-only) diarrheal episodes. Economic analyses made in the United States indicate that a vaccine that costs less than US$ 9 per dose would lead to a net savings in medical costs. To date, however, cost-benefit studies have not been done in developing countries. In the future, it is possible that some Latin American countries might adapt their polio production facilities to the preparation of rotavirus vaccines for human use. A year after RRV-TV was licensed for vaccination of infants in the United States, the occurrence of intussusception as an adverse event led to the vaccine's withdrawal from the market. The implications of that action, particularly for Latin America, will be addressed in this article, including the need to explore alternative rotavirus candidate vaccines, particularly through the conduct of parallel clinical trials in both developed and developing countries.