Mapping the high burden areas of cholera in Nepal for potential use of oral cholera vaccine: An analysis of data from publications and routine surveillance systems

Objective: To assess the extent of existing published evidence on cholera and to characterize the epidemiologic data of cholera in Nepal. Methods: We conducted a literature scoping review by summarizing published literature reporting on cholera in Nepal from January 1946 to March 2019 in online databases: MEDLINE, Embase, Cochrane, and Global Health. Additionally, we reviewed national surveillance data on clinically diagnosed and laboratory confirmed cholera reported by the Ministry of Health and Population. Results: Most of the published studies were conducted predominantly in Kathmandu Valley during the rainy season; however, outbreaks have been reported in other parts of Nepal including Terai, Hilly and Mountain regions. Our literature review exhibited that all age groups were affected by cholera, but particularly children and young adults were at-risk age groups in Nepal. Vibrio cholerae serogroup O1, biotype El Tor, serotype Ogawa has been predominantly isolated with an emergence of resistant strains since 1996. Two mass vaccination campaigns using oral cholera vaccines were conducted: Rautahat district in 2014 and Banke district in 2017. Conclusions: Capacity building for a nation wide systematic cholera surveillance with rapid and reliable diagnosis is needed to better estimate the burden of cholera and identify geographically at-risk areas associated with the disease in Nepal. It is essential for developing an adequate policy on oral cholera vaccine introduction and effective water, sanitation and hygiene interventions.

Mapping the high burden areas of cholera in Nepal for potential use of oral cholera vaccine: An analysis of data from publications and routine surveillance systems

Objective: To assess the extent of existing published evidence on cholera and to characterize the epidemiologic data of cholera in Nepal. Methods: We conducted a literature scoping review by summarizing published literature reporting on cholera in Nepal from January 1946 to March 2019 in online databases: MEDLINE, Embase, Cochrane, and Global Health. Additionally, we reviewed national surveillance data on clinically diagnosed and laboratory confirmed cholera reported by the Ministry of Health and Population. Results: Most of the published studies were conducted predominantly in Kathmandu Valley during the rainy season; however, outbreaks have been reported in other parts of Nepal including Terai, Hilly and Mountain regions. Our literature review exhibited that all age groups were affected by cholera, but particularly children and young adults were at-risk age groups in Nepal. Vibrio cholerae serogroup O1, biotype El Tor, serotype Ogawa has been predominantly isolated with an emergence of resistant strains since 1996. Two mass vaccination campaigns using oral cholera vaccines were conducted: Rautahat district in 2014 and Banke district in 2017. Conclusions: Capacity building for a nation wide systematic cholera surveillance with rapid and reliable diagnosis is needed to better estimate the burden of cholera and identify geographically at-risk areas associated with the disease in Nepal. It is essential for developing an adequate policy on oral cholera vaccine introduction and effective water, sanitation and hygiene interventions.

Safety and Immunogenicity Assessment of an Oral Cholera Vaccine through Phase I Clinical Trial in Korea

The safety, tolerability and immunogenicity of an oral cholera vaccine (OCV) was assessed in adult Korean male through an open-label, non-comparative clinical study. Two doses of vaccine with an interval of 2 weeks were given to 20 healthy subjects. A total of 7 adverse events occurred in 6 subjects. However, no clinically significant change was observed in electrocardiograms, vital signs, physical examinations, and clinical laboratory tests. The immunogenicity of OCV was evaluated by serum vibriocidal assay where anti-Vibrio cholerae O1 and O139 antibodies were measured at day 0, 14, and 28 of vaccine administration. The antibody titers ranged from < 2.5-5,120 for V. cholerae O1 Inaba, < 2.5-10,240 for V. cholerae O1 Ogawa and < 2.5-480 for V. cholerae O139. In addition, the fold increase in antibody titers ranged from 1-4,096 for O1 Inaba, 1-8,192 for O1 Ogawa, and 1-384 for O139. The seroconversion rate was 95% and 45% for O1 and O139 antibodies, respectively. Our study clearly shows that administration of two doses of OCV at a 2 week-interval increases an appropriate level of antibody titer in the serum of healthy Korean adult males (Clinical Trial Number, NCT01707537).

Vaccines today, vaccines tomorrow: a perspective

Vaccines are considered as one of the major contributions of the 20th century and one of the most cost effective public health interventions. The International Vaccine Institute has as a mission to discover, develop and deliver new and improved vaccines against infectious diseases that affects developing nations. If Louis Pasteur is known across the globe, vaccinologists like Maurice Hilleman, Jonas Salk and Charles Merieux are known among experts only despite their contribution to global health. Thanks to a vaccine, smallpox has been eradicated, polio has nearly disappeared, Haemophilus influenzae B, measles and more recently meningitis A are controlled in many countries. While a malaria vaccine is undergoing phase 3, International Vaccine Institute, in collaboration with an Indian manufacturer has brought an oral inactivated cholera vaccine to pre-qualification. The field of vaccinology has undergone major changes thanks to philanthropists such as Bill and Melinda Gates, initiatives like the Decade of Vaccines and public private partnerships. Current researches on vaccines have more challenging targets like the dengue viruses, malaria, human immunodeficiency virus, the respiratory syncytial virus and nosocomial diseases. Exciting research is taking place on new adjuvants, nanoparticles, virus like particles and new route of administration. An overcrowded infant immunization program, anti-vaccine groups, immunizing a growing number of elderlies and delivering vaccines to difficult places are among challenges faced by vaccinologists and global health experts.

A 6-Week Oral Toxicity Study of Oral Cholera Vaccine in Sprague-Dawley Rats

The present study was carried out to examine the toxicity and target organs of oral cholera vaccine (OCV) after repeated oral administration in Sprague-Dawley rats for 6 weeks (3 administrations, once every 2 weeks). OCV is an inactivated oral cholera vaccine that contains Vibrio cholerae and confers protection against cholera caused by V. cholera serogroups O1 (Inaba and Ogawa serotypes) and O139 (strain 4260B). The animals were orally administered either OCV placebo (negative control) or OCV at a dose equivalent to 240 times the anticipated human dose. Throughout the administration period, no significant change was detected in clinical signs, body weight, food or water consumption, urinalysis results, hematological and clinical biochemistry test results, organ weights, necropsy, or histopathological examination results. Minor changes were found in hematological and clinical biochemistry tests; however, these changes were within normal ranges. The above results suggest that oral administration of OCV in rats did not induce any toxicologically meaningful changes, and the target organs could not be determined. This study was conducted in accordance with the guidelines established by Good Laboratory Practice (2009-183, KFDA, December 22, 2009) and the OECD Principles of Good Laboratory Practice (1997).

Cholera toxin – A foe & a friend.

After De’s pivotal demonstration in 1959 of a diarrhoeogenic exo-enterotoxin in cell-free culture filtrates from Vibrio cholerae (of classical biotype), much insight has been gained about cholera toxin (CT), which is arguably now the best known of all microbial toxins. The subunit structure and function of CT, its receptor (the GM1 ganglioside), and its effects on the cyclic AMP system and on intestinal secretion were defined in the 1970s, and the essential aspects of the genetic organization in the 1980s. Recent findings have generated additional perspectives. The 3D-crystal structure of CT has been established, the CT-encoding operon has been shown to be carried by a non-lytic bacteriophage, and in depth knowledge has been gained on how the bacterium controls CT gene expression in response to cell density and various environmental signals. The mode of entry into target cells and the intracellular transport of CT are becoming clearer. CT has become the prototype enterotoxin and a widely used tool for elucidating important aspects of cell biology and physiology, e.g., cell membrane receptors, the cyclic AMP system, G proteins, as well as normal and pathological ion transport mechanisms. In immunology, CT has emerged as a potent, widely used experimental adjuvant, and the strong oral-mucosal immunogenicity of the non-toxic B-subunit (CTB) has led to the use of CTB as a protective antigen together with killed vibrios in a widely licensed oral cholera vaccine. CTB has also been shown to promote immunological tolerance against certain types of mucosally co-administered antigens, preferably tissue antigens linked to the CTB molecule; this has stimulated research and development to use CTB in this context for treatment of autoimmune and allergic diseases. In summary, in the 50 years after De’s discovery of CT, this molecule has emerged from being the cholera patient’s “foe” to also becoming a highly useful scientist’s “friend”.

Vaccines for Diarrheal Diseases / 소아감염

Diarrhea is one of the most common causes of morbidity and mortality in children worldwide. Rotavirus is the most common cause of infectious diarrhea both in developed and developing countries. However, bacterial causes such as Salmonella typhi and Vibrio cholerae still play an important role in developing countries. Newly developed vaccines for rotavirus, S. typhi, and V. choleae are highly immunogenic and safe in children.

Effectiveness of oral cholera vaccine three to five years after mass vaccination in Hue

From 1998, mass immunization using the locally-produced, killed oral cholera vaccine was conducted in half of the communes of Hue city followed by mass immunization of the remaining communes in 2000. In 2003, a cholera outbreak occurred in the city. The objective of the study is to assess the effects of vaccine after 3-5 years. The control group had the same address, sex and age with cholera patients. From May – August 2003, a total of 115 confirmed cholera cases were detected in Hue city. In this study, 48 cases were positive culture-confirmed and 21 cases was clinically suspected cholera. 62% cases had been vaccinated compared with 75% of the controls. The results showed that, using cholera vaccine in 1998 or 2000 conferred 50% protection against cholera during the 2003 outbreak

Chemical composition of oral cholera vaccine 2001-2002

At Cho Ray Hospital – Ho Chi Minh city from Dec 2001 to Dec 2002, 228 heart failure cases (96 males, 130 females, aged 58.4317.45) were studied. Their associated conditions were: 14 with diabetes, 5 brain blood infactus, 5 hyperthyroidies, 19 kidney failures. Among 162 patients with electrolyte disorders, 25 were died, the rate of hyponatremia and hyperkalemia was significantly higher in fatal group than in survival group. Hyponatremia was fatal risk factor and it should pay great attention to treat this condition with hypertonic natrium solution

Chemical composition of oral cholera vaccine 2001-2002

19 lots of oral vaccine producted in the years 2001-2002 at the Company No1 of Vaccines and Biological Preparations were studied. pH=6.9 in the lot 110102, the highest was 7.3 in the lots 050901, 060901 and 091201 (permissible pH=6.8-7.4); thimerosant content from 0.005 g% in the lot 020801 to 0.015 g% in the lots 110102, 120302 and 150502 (permissible content ≤ 0.02 g%); formaldehyde content from 0.005 g% in the lot 060901 to 0.017 g% in the lot 110102 (permissible content ≤ 0.02 g%); total protein content 0.77 g% in the lot 091201 and 1.63 g% in the lot 181002 (permissible content ≤ 2 g%)

On the safety of oral cholerae vaccine produced at Company No1 of Vaccine and Biological Preparation

During 2001-2002 period, 19 lots of oral cholera vaccines were prepared at the Company No1 of Vaccine and Biological Preparation. Weight gain tests were performed on white mice, each test used 20 mices for vaccine sample and 20 mices for control. According to WHO standards and Central National of Control for Biological Preparation standards, cholera vaccine does not cause death for mice, and mean weight of mouse after three days injection is at least equal to that of infection moment and the mean weight gain of the seventh day is higher or equal 60% of control. All 19 lots of vaccine had had high safety

Estudio del patrón de excresión y la capacidad protectora en conejos inmunizados de forma oral con cepas atenuadas de Vibrio cholerae O1 biotipo El Tor

Con el fin de estudiar los patrones de excreción, colonización y la capacidad protectora de cepas vivas atenuadas de Vibrio cholerae O1El Tor, se inmunizaron conejos Nueva Zelandia con estas cepas y su correspondiente parental, con 2 dosis por el modelo de inoculación oral en conejos adultos. Fueron retados 2 semanas después de la segunda dosis por el modelo de intestino ligado, con cepas altamente virulentas de V. choleraeO1 serotipos Ogawa e Inaba y serogrupo O139. Se comprobó que las cepas manupuladas de forma genética no afectan los patrones de excreción, cuando se compara con su parental. Se observó en el reto una disminución en los niveles de colonización de las cepas virulentas de ambos serotipos; tanto en los conejos inmunizados con las cepas atenuadas como con la parental en comparación con animales controles inmunizados con la cepa Escherichia coli K-12, lo que indica que hubo cierto grado de protección. En el caso de los animales retados con la cepa 0139 se demostró que la protección es específica para cada serogrupo pues en este caso no se observó disminución de la colonización.

In order to study the excretion patterns, colonization and protective capacity of live sttenuated strains of Vibrio cholerae O1. E1 Tor, rabbits were immunized in New Zealand with these strains and their corresponding parental strains. 2 doses were administered by the model of oral inoculation in adult rabbits. Rabbits were rotated 2 weeks after the second dose by the model of ligated intestine with highly virulent strains of V. cholerae O1 Ogawa and Inaba serotypes and O139 serogroup. It was proved that the genetically manipulated strains do not effect the excretion patterns when they are compared with their parental strains. It was observed in the challenge a decrease in the levels of colonization of virulent strains of both serotypes, not only among the rabbits immunized with the attenuated strains, but also among those immunizedwith the parental strains in comparison with control animals immunized with the strain of Escherichia coli K-12, which means that there was certain degree of protection. In the case of the animals challenged with the O139 strain it was demonstrated that the protection is specific for each serogroup, since in this case there was no reduction of the colonization.