Vivotif Berna

VIVOTIF BERNA™

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. Many 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, North and Central Africa, 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 non-symptomatic 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 bloodstream, thereby causing disease. The risk of severe illness is increased in the absence of gastric acid, e.g., prior gastrectomy, antacid therapy, H2 antagonists, or in immunocompromised hosts. 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 undergoing 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 has 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 prepared 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 strain has been evaluated in a series of double-blind field trials. The first trial was performed in Alexandria, Egypt with a study population of 32 388 children aged 6 to 7 years. 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 series of field trials was subsequently performed in Santiago, Chile to evaluate efficacy when the vaccine strain was administered 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 enteric-coated capsules 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. After 48 months of surveillance, the short immunization schedule resulted in a 68% decrease in typhoid fever. 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 within the 3 vaccinated groups was highest for the 4-dose regimen.

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

Indications And Clinical Uses: For immunization of adults and children greater than 5 years of age against disease caused by S. typhi. Results from clinical studies indicate that adults and children greater than 5 years of age may be protected against typhoid fever following the oral ingestion of 4 doses of Typhoid Vaccine Live Oral Attenuated Ty21a. Immunization (ingestion of all 4 doses of Typhoid Vaccine Live Oral Attenuated Ty21a) 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) close continuing exposure to an S. typhi carrier such as occurs in members of a household or institution in which a carrier lives; 2) travel to countries where typhoid fever is endemic; 3) laboratory workers who frequently handle cultures of S. typhi.

Not all recipients of Typhoid Vaccine Live Oral Attenuated Ty21a 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 sources.

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.

Typhoid Vaccine Live Oral Attenuated Ty21a will not afford protection against enteric organisms other than S. typhi.

There are no studies reported using Typhoid Vaccine Live Oral Attenuated Ty21a 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 4 vaccine capsules 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 to 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 such 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 enteric-coated capsule.

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).

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 component or medium component (see Supplied).

The antimalarial drug mefloquine does inhibit the growth of the Ty21a vaccine strain in vitro with a minimal inhibitory concentration (MIC) of 5 to 10 µg/mL. Mefloquine is rapidly absorbed from the intestinal tract (T1/2 of 0.36 to 2 hours). It is reasonable to expect that the level of mefloquine would drop below the MIC for the vaccine strain by 8 hours after ingestion. It is therefore recommended that Thyphoid Vaccine Live Oral Attenuated Ty21a be administered at least 8 hours after mefloquine. No human studies are available to document that the above recommended dosing schedule does not adversely affect the immunogenicity of Typhoid Vaccine Live Oral Attenuated Ty21a. The MIC of chloroquine for the Ty21a vaccine strain is >200 µg/mL. While no in vitro inhibitory effect of chloroquine has been shown for the Ty21a vaccine strain, is is recommended that chloroquine be administered at least 8 hours prior to Typhoid Vaccine Live Oral Attenuated Ty21a.

Information for the Patient: It is essential that all 4 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 capsule should be swallowed approximately 1 hour before a meal with a cold or lukewarm drink (temperature not to exceed body temperature, i.e., 37°C). Care should be taken not to chew the vaccine capsule. After placing in the mouth, the vaccine capsule should be swallowed as soon as possible.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals with Typhoid Vaccine Live Oral Attenuated Ty21a have not been performed to evaluate carcinogenic potential, mutagenic potential or impairment of fertility.

Pregnancy: Category C: Animal reproduction studies have not been conducted with Typhoid Vaccine Live Oral Attenuated Ty21a. It is not known whether Typhoid Vaccine Live Oral Attenuated Ty21a can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Typhoid Vaccine Live Oral Attenuated Ty21a 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 Typhoid Vaccine Live Oral Attenuated Ty21a is excreted in human milk.

Children: The safety of Typhoid Vaccine Live Oral Attenuated Ty21a has not been established in children under 6 years of age. This product is therefore not recommended for use in children under 6 years of age.

Adverse Reactions: Several lots of Typhoid Vaccine Live Oral Attenuated Ty21a have been evaluated in several field trials both in adults and in school-aged children. Objectively monitored side effects, e.g., abdominal pain, diarrhea, vomiting, fever, headache and skin rash, did not occur at a statistically higher frequency in the vaccinated group as compared to the placebo group. Postmarketing surveillance outside of the United States has found that side effects are infrequent, transient, and resolve of their own accord. Reported adverse reactions include nausea, abdominal cramps, vomiting, skin rash or urticaria in the trunk and/or extremities.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: 5 to 8 doses of Typhoid Vaccine Live Oral Attenuated Ty21a containing between 3 to 10´100viable vaccine organisms were administered to 155 healthy adult males. This dosage was, at a minimum, 5-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: 1 capsule is to be swallowed approximately 1 hour before a meal with a cold or lukewarm drink (temperature not to exceed body temperature, i.e., 37°C) on alternate days, e.g., days 1, 3, 5 and 7. The vaccine capsule should not be chewed and should be swallowed as soon as possible after placing in the mouth. A complete immunization schedule is the ingestion of 4 vaccine capsules as described above. Unless a complete immunization schedule is followed, an optimum immune response may not be achieved. Not all recipients of Typhoid Vaccine Live Oral Attenuated Ty21a 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.

Booster Use: The optimum booster schedule for Typhoid Vaccine Live Oral Attenuated Ty21a has not been determined. Efficacy has been shown to persist for at least 7 years. Further, there is no experience with Typhoid Vaccine Live Oral Attenuated Ty21a as a booster in persons previously immunized with parenteral typhoid vaccine. Despite these limitations, it is recommended that a booster dose consisting of 4 vaccine capsules taken on alternate days be given every 7 years under conditions of repeated or continued exposure to typhoid fever.

Availability And Storage: Each enteric-coated capsule contains: viable S. typhi Ty21a 2 to 10´10colony-forming units, non-viable S. typhi Ty21a 5 to 60´10bacterial cells, sucrose 16.7 to 41.7 mg, ascorbic acid 0.6 to 1.6 mg, amino acid mixture 0.8 to 2.1 mg, lactose 135.8 to 166.6 mg and magnesium stearate 3.4 to 4.2 mg. Single foil blisters of 4. The blister containing the vaccine capsules should be inspected to ensure that the foil seal and the capsules are intact.

Typhoid Vaccine Live Oral Attenuated Ty21a 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.

VIVOTIF BERNA™ Berna Products Typhoid Vaccine Live Oral Attenuated Ty21a Typhoid Prophylaxis

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