Vivotif Berna L Vaccine

VIVOTIF BERNA® L VACCINE

Berna Products

Typhoid Vaccine Live Oral Attenuated Ty21a

Typhoid Prophylaxis

Action And Clinical Pharmacology: S. typhi is the etiological agent of typhoid fever, an acute, febrile enteric disease. This vaccine will not afford protection against species of Salmonella other than S. typhi or other bacteria that cause enteric disease.

The incidence of typhoid fever has declined steadily in Canada. Approximately 70 cases are reported annually. Most of these infections were contracted abroad, but a small number occur in Canada, chiefly in areas where sanitation and hygiene are inadequate. There are approximately 500 cases of typhoid fever per year diagnosed in the United States. In 62% of these patients (statistics from 1977 to 1979) the disease was acquired outside of the United States, while in 38% of the patients the disease was acquired within the United States. Of the disease acquired during foreign travel, 50% of the cases were contracted in Mexico, 20% in Asian countries, and 15% in India. The majority of the remaining cases were acquired in the Caribbean basin, South and Central America, North Africa, and Southern Europe. Typhoid fever is considered to be endemic in most areas of Central and South America, the African continent, the Near East and the Middle East, Southeast Asia and the Indian subcontinent. Of the disease acquired in the United States, 23% of the cases were associated with typhoid carriers, 24% were due to food outbreaks, 23% were associated with the ingestion of contaminated food or water, 6% due to household contact with an infected person, and 4% following exposure to S. typhi in a laboratory setting.

The majority of typhoid cases respond favorably to antibiotic therapy. However, the emergence of chloramphenicol-or ampicillin-resistant strains has greatly complicated therapy. Even with appropriate antibiotic therapy, there were 7 deaths among 901 acute typhoid cases reported in the United States from 1977 to 1979. Approximately 3 to 5% of acute typhoid cases result in the development of a chronic carrier state. These nonsymptomatic carriers are the natural reservoir for S. typhi and can serve to maintain the disease in its endemic state or to directly infect individuals. Eradication of the carrier state by antibiotic therapy has been unsuccessful. The effect of immunization with Typhoid Vaccine Live Oral Attenuated Ty21a on the carrier state is unknown.

Upon ingestion, virulent strains of S. typhi are able to pass through the stomach acid barrier, colonize the intestinal tract, penetrate the lumen and enter the lymphatic system and blood stream, thereby causing disease. The risk of severe illness is increased in the absence of gastric acid, e.g., prior gastrectomy, antacid therapy, H2 antagonist therapy, or in immunocompromised individuals. One possible mechanism by which disease may be prevented is by evoking a local immune response in the intestinal tract. Such local immunity may be induced by oral ingestion of a live attenuated strain of S. typhi which causes an aborted infection.

The ability of S. typhi to cause disease and to induce a protective immune response is dependent upon the bacteria possessing a complete lipopolysaccharide. The S. typhi Ty21a vaccine strain, derived by chemical mutagenesis, is entirely deficient in activity of the gal E gene product, which restricts its ability to produce complete lipopolysaccharide. In addition, Ty21a has several nutritional auxotrophies, has approximately half the growth rate of the parent strain Ty2, does not produce H2S, and lacks the Vi antigen (capsular acidic polysaccharide present on almost all virulent S. typhi strains). Ty21a, grown in the presence of low concentrations of galactose, is immunogenic, suggesting that the uptake of galactose by Ty21a enables production of lipopolysaccharide, leading to immunogenicity. It has been presumed that an oversupply of galactose results in accumulation of toxic metabolites within the bacterial cells leading to bacterial lysis. Attenuation and safety of Ty21a have been presumed to be due to the combination of gal E mutation and the lack of Vi antigen. However, an analogous mutant (Vi negative, gal E deletion mutant) of S. typhi constructed by recombinant DNA techniques has been shown to be virulent. In addition, galactose induced lysis of Ty21a is inhibited in vitro in the presence of glucose. Therefore, the combination of gal E and Vi mutations does not account for the safety of Ty21a or for the failure to recover vaccine organisms from people ingesting the usual dose. Ty21a is attenuated by an incompletely understood mechanism.

The efficacy of the S. typhi Ty21a vaccine strain has been evaluated in a series of randomized, double-blind, placebo-controlled field trials. A trial was performed in Plaju, Indonesia, with a study population of 20 543 subjects aged 3 to 44 years. The subjects were randomized to receive either 3 doses of vaccine, either in sachets or enteric-coated capsules, or an identical appearing placebo. Each dose of vaccine was administered 1 week apart. After 30 months of passive surveillance, vaccine efficacy was determined to be 53% (95% confidence interval: 36 to 66%) for Vivotif Berna L Vaccine and 42% (95% confidence interval: 23 to 57%) for Vivotif Berna Vaccine (enteric-coated capsules). The difference in the overall degree of protection conferred against typhoid fever by the 2 different vaccine presentations was not statistically significant. A second trial of similar design was conducted in Santiago, Chile, with a study population of 81 621 school children aged 5 to 19 years. Protection against typhoid fever in all age groups after 36 months of passive surveillance was 76.9% (95% confidence interval: 60 to 87%) for Vivotif Berna L Vaccine versus 33.2% (95% confidence interval: 0 to 57%) for the enteric-coated Vivotif Berna Vaccine formulation. The difference in protection rates was highly significant (p9 years of age), Vivotif Berna Vaccine was ineffective in younger children.

The efficacy of the S. typhi Ty21a vaccine strain has been evaluated in several additional double-blind, randomized field trials. The first was performed in Alexandria, Egypt, with a study population of 32 388 children 6.5 to 7 years of age. Three doses of vaccine, in the form of a freshly reconstituted suspension administered after ingestion of 1 g of bicarbonate, were given on alternate days. Immunization resulted in a 95% decrease in the incidence of typhoid fever over a 3-year period of surveillance. A further series of field trials was subsequently performed in Santiago, Chile, to evaluate efficacy where the vaccine was administered only in the form of an acid-resistant enteric-coated capsule. The initial trial involved 91 954 school-aged children, and compared 1 or 2 doses of vaccine given 1 week apart. After 33 months of passive surveillance, vaccine efficacy was 21% for the single dose schedule and 54% for the 2-dose schedule. A further field trial was performed in Santiago, Chile, involving 109 594 school-aged children. Three doses of vaccine were administered either on alternate days (short immunization schedule) or 21 days apart (long immunization schedule). Following 36 months of surveillance, vaccination resulted in a 67% decrease in the incidence of typhoid fever in the short immunization schedule group and a 49% reduction in the long immunization schedule group. Following 7 years of surveillance, vaccine efficacy was found to be 62.8% for the short immunization schedule. A field trial was next conducted in Santiago, Chile, to determine the relative efficacy of 2, 3 and 4 doses of enteric-coated vaccine administered on alternate days to school-aged children. Relative vaccine efficacy, as determined by comparison of disease incidence between the 3 vaccinated groups, was highest for the 4-dose schedule. The sum total of the above results indicates that 3 doses of Vivotif Berna L Vaccine provide a level of protection comparable to that obtained after vaccination with 4 doses of Vivotif Berna Vaccine (enteric-coated capsules).

The efficacy of the S. typhi Ty21a vaccine strain has been demonstrated only in areas of the world where typhoid fever is endemic. Efficacy has not been demonstrated for individuals residing in a nontyphoid fever endemic area who then enter a typhoid fever endemic area. Ingestion of 3 doses of Ty21a vaccine induced comparable levels of anti-S. typhi lipopolysaccharide serum antibody levels in healthy young adults living in endemic (Chile) or nonendemic (United States, Austria and Switzerland) areas. However, the significance of this antibody response as it relates to vaccine-induced protection against typhoid fever is not known.

Indications And Clinical Uses: For immunization of adults and children 3 years of age and older against disease caused by S. typhi. Results from clinical studies indicate that adults and children 3 years of age or older may be protected against typhoid fever following the oral ingestion of 3 doses of Vivotif Berna L Vaccine. Immunization (ingestion of all 3 doses) should be completed at least 1 week prior to potential exposure to S. typhi.

Routine typhoid vaccination is not recommended in Canada but immunization should be considered in the following situations: 1) travel in endemic areas for extended periods, or off the usual tourist tracks; 2) ongoing household or intimate exposure to a typhoid carrier; 3) laboratory workers who frequently handle cultures of S. typhi.

Not all recipients of Vivotif Berna L Vaccine will be fully protected against typhoid fever. Travelers should take all necessary precautions to avoid contact with or ingestion of potentially contaminated food or water. There is no evidence to support the use of typhoid vaccine to control common source outbreaks, disease following natural disasters or in persons attending rural summer camps. Vivotif Berna L Vaccine will not afford protection against enteric organisms other than S. typhi.

There are no studies reported using Vivotif Berna L Vaccine as a booster for persons previously vaccinated with the parenteral vaccine. An optimal booster dose has not yet been established. However, it is recommended that a booster dose consisting of 3 double-chambered sachets taken on alternate days be given every 7 years under conditions of repeated or continued exposure to typhoid fever (see Dosage).

Typhoid fever continues to be an important disease in many parts of the world. Travelers entering such areas are at risk of contracting typhoid fever following the ingestion of contaminated food or water. Parenterally administered typhoid vaccine has been shown to be effective at reducing the incidence of disease in endemic areas. However, immunization with such vaccines is frequently accompanied by adverse reactions such as pain and/or swelling at the injection site, fever, malaise and headache.

Contra-Indications: Hypersensitivity to any component of the vaccine or the buffer. Safety of the vaccine has not been demonstrated in persons deficient in their ability to mount a humoral or cell-mediated immune response due to either a congenital or acquired immunodeficient state, including treatment with immunosuppressive or antimitotic drugs. The vaccine should not be administered to these persons regardless of benefits.

Manufacturers’ Warnings In Clinical States: Typhoid Vaccine Live Oral Attenuated Ty21a is not to be taken during an acute febrile illness or in the face of acute gastrointestinal illness or chronic inflammatory bowel disease. Postpone taking the vaccine if persistent diarrhea or vomiting is occurring (see Precautions, General).

Phenylketonurics: contains phenylalanine (17 mg per double-chambered sachet). This is due to the fact that Vivotif Berna L Vaccine is sweetened by aspartame (a phenylalanine derivative).

Precautions: General: The vaccine should not be administered to persons during an acute febrile illness or acute gastrointestinal illness. The vaccine should not be administered to individuals receiving antibiotics (sulfonamides included) since these agents may be active against the vaccine strain and prevent a sufficient degree of multiplication to occur in order to induce a protective immune response. The vaccine should not be administered to persons with a known hypersensitivity to any vaccine, buffer or medium component (see Supplied). Several antimalaria drugs, such as mefloquine, chloroquine and proguanil possess antibacterial activity which may interfere with the immunogenicity of Vivotif Berna L Vaccine. To determine the effect of these antimalaria drugs on the humoral anti-S. typhi immune response, healthy adult subjects were given mefloquine (250 mg at weekly intervals; N=30) chloroquine (500 mg at weekly intervals; N=30) or proguanil (200 mg daily; N=30) together with Vivotif Berna L Vaccine. Concomitant treatment with mefloquine or chloroquine did not result in a significant (p>0.05) reduction in the serum anti-S. typhi immune response compared to subjects receiving vaccine only (N=45). The simultaneous administration of proguanil did effect a significant (p=0.013) decrease in the immune response rate. These findings indicate that mefloquine and chloroquine can be administered together with Vivotif Berna L Vaccine. Proguanil should be administered only if 10 days or more have elapsed since the final dose of Vivotif Berna L Vaccine was ingested. If Vivotif Berna L Vaccine and Mutacol Berna Vaccine (Cholera Vaccine Live Oral CVD 103-HgR) are taken together (see below) only mefloquine should be used for malaria prophylaxis due to the fact that chloroquine has been shown to suppress the immune response engendered by Mutacol Berna Vaccine.

The concomitant administration of oral polio vaccine or yellow fever vaccine did not suppress the immune response elicited by Vivotif Berna L Vaccine. There is no reason to believe that simultaneous administration of parenteral vaccines or immunoglobulins with Vivotif Berna L Vaccine will decrease vaccine efficacy. Vivotif Berna L Vaccine and Mutacol Berna Vaccine can be simultaneously administered safely without adversely affecting the immune response to either vaccine. Mutacol Berna Vaccine should be combined with the first dose of Vivotif Berna L Vaccine as this dosing schedule has been shown to elicit an optimal immune response to both vaccines. If taken together, a single sachet of Vivotif Berna L Vaccine and Mutacol Berna Vaccine should be reconstituted in the following way: The contents of the vaccine chamber (chamber B) of both vaccines are mixed with the contents of one buffer chamber (chamber A) in 100 mL of cold or lukewarm water (see Dosage). Alternatively, Vivotif Berna L Vaccine and Mutacol Berna Vaccine can be administered separately with an interval of greater than 4 hours between vaccinations. This is to allow the gastric acidity to return to normal levels between dosing.

Information to be Provided for the Patient: It is essential that all 3 doses of vaccine be taken at the prescribed alternate day interval to obtain a maximal protective immune response. Vaccine potency is dependent upon storage under refrigeration (between 2 and 8°C). The vaccine should be stored under refrigeration at all times. It is essential to replace unused vaccine in the refrigerator between doses. The vaccine is to be reconstituted and ingested in the following manner: First, gently shake or tap the sachet to ensure that the contents have settled to the bottom. Fold the sachet in half as depicted in step 1 shown on the reverse side of the sachet. Cut along the dotted line as shown in step 2. Carefully empty the entire contents of both sachet chambers into 100 mL of cold or lukewarm water (temperature not to exceed body temperature, i.e., 37°C). The vaccine is not to be reconstituted in carbonated beverages, fruit juices or milk. Gently stir (5 to 10 seconds) the mixture with a spoon or other appropriate utensil until a homogenous suspension is obtained. The vaccine should be swallowed as soon as possible thereafter.

Phenylketonurics: contains phenylalanine (17 mg per double-chambered sachet). This is due to the fact that Vivotif Berna L Vaccine is sweetened by aspartame (a phenylalanine derivative).

Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals with Vivotif Berna L Vaccine have not been performed to evaluate carcinogenic potential, mutagenic potential or impairment of fertility.

Pregnancy: Animal reproduction studies have not been conducted with Vivotif Berna L Vaccine. It is not known whether Vivotif Berna L Vaccine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Vivotif Berna L Vaccine should be given to a pregnant woman only if clearly needed.

Lactation: There are no data to support the use of this product in nursing mothers. It is not known if Vivotif Berna L Vaccine is excreted in human milk.

Children: The safety of Vivotif Berna L Vaccine has not been established in children under 3 years of age. This product is therefore not recommended for use in children under 3 years of age.

Adverse Reactions: Several lots of Vivotif Berna L Vaccine have been evaluated in field trials both in children and adults. There were no statistically significant differences for objectively monitored side effects, e.g., abdominal pain, diarrhea, vomiting, fever, nausea, except the higher incidence of skin rash in vaccine recipients versus placebo group. Objectively monitored side effects did not occur at a statistically higher frequency among 2- to 6-year-old Thai children or adult Europeans who received the vaccine as compared to a placebo group.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Five to 8 doses of the vaccine strain Ty21a containing between 3 to 10´100viable vaccine organisms were administered to 155 healthy adult males. This dosage was, at a minimum, 3-fold higher than the currently recommended dose. No significant reactions, e.g., vomiting, acute abdominal distress or fever, were observed. At the recommended dosage, the S. typhi Ty21a vaccine strain is not excreted in the feces. However, clinical studies in volunteers have shown that overdosing can increase the possibility of shedding the S. typhi Ty21a vaccine strain in the feces.

Dosage And Administration: The vaccine is to be taken approximately 1 hour before a meal as described below. A complete immunization schedule is the ingestion of 3 double-chambered sachets taken on alternate days. Unless a complete immunization schedule is followed, an optimum immune response may not be achieved. Not all recipients of Vivotif Berna L Vaccine will be fully protected against typhoid fever. Travelers should take all necessary precautions to avoid contact with or ingestion of potentially contaminated food or water.

The sachet containing the buffer (chamber A) and vaccine (chamber B) should be inspected to ensure that the foil is intact. Reconstitution of the vaccine is performed in the following manner: The sachet is to be folded along the solid black line and cut along the dotted line after insuring that the contents have been displaced to the bottom to prevent spillage. The contents of both chambers are to be emptied simultaneously into 100 mL of cold or lukewarm water (temperature not to exceed body temperature, e.g., 37°C). Do not resuspend in milk, juice or in a carbonated beverage. Resuspend the sachet contents by gently mixing for 5 to 10 seconds. The vaccine should be swallowed as soon after mixing as possible.

Booster Use: The optimum booster schedule for Vivotif Berna L Vaccine has not been determined. Efficacy has been shown to persist for at least 7 years. However, there is no experience with Vivotif Berna L Vaccine as a booster in persons previously immunized with parenteral typhoid vaccine. Despite these limitations, it is recommended that a booster dose consisting of 3 double-chambered sachets taken on alternate days be given every 7 years under conditions of repeated or continued exposure to typhoid fever.

Availability And Storage: Vivotif Berna L Vaccine (Typhoid Vaccine Live Oral Attenuated Ty21a) is a live attenuated vaccine for oral administration. The vaccine contains the attenuated strain S. typhi Ty21a.

Vivotif Berna L Vaccine is manufactured by the Swiss Serum and Vaccine Institute Berne. The vaccine strain is grown under controlled conditions in a medium containing yeast extract, an acid digest of casein, dextrose and galactose. The bacteria are collected by centrifugation, mixed with a stabilizer containing sucrose, ascorbic acid and amino acids, and lyophilized. The lyophilized bacteria are mixed with lactose and aspartame and filled into 1 chamber of a double-chambered aluminum foil sachet. A sodium bicarbonate-ascorbic acid buffer is filled into the second chamber and the sachet is sealed. Each double-chambered sachet contains: buffer chamber A: sodium bicarbonate 2.4-2.9 g, ascorbic acid 1.5-1.8 g and lactose 0.18-0.22 g; vaccine chamber B: viable S. typhi Ty21a 2-10´10colony-forming units, nonviable S. typhi Ty21a 5-60´10bacterial cells, sucrose 15-250 mg, amino acid mixture 0.8-15 mg, ascorbic acid 0.6-10 mg, aspartame 20-30 mg and lactose 1.5-2.1 g.

Packages of 3 double-chambered aluminum foil sachets each containing 1 dose of vaccine. The contents of each chamber require simultaneous reconstitution prior to oral administration.

The vaccine is not stable when exposed to ambient temperatures. The vaccine should therefore be shipped and stored between 2 and 8°C. Each package of vaccine shows an expiration date. This expiration date is valid only if the product has been maintained between 2 and 8°C. Store in a dry place and protect from light.

VIVOTIF BERNA® L VACCINE Berna Products Typhoid Vaccine Live Oral Attenuated Ty21a Typhoid Prophylaxis

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