Label: TYPHIM VI- salmonella typhi ty2 vi polysaccharide antigen injection, solution

AHFS Category: 80:12

Typh

Rx only

Typhim Vi®, Typhoid Vi Polysaccharide Vaccine, produced by Sanofi Pasteur SA, for intramuscular use, is a sterile solution containing the cell surface Vi polysaccharide extracted from Salmonella enterica serovar Typhi, S typhi Ty2 strain. The organism is grown in a semi-synthetic medium. Casein derived raw materials are used early in manufacturing during the fermentation process. The capsular polysaccharide is precipitated from the concentrated culture supernatant by the addition of hexadecyltrimethylammonium bromide, and the product is purified by differential centrifugation and precipitation. Each 0.5 mL dose may contain residual amounts of formaldehyde (not more than 100 mcg) used for the inactivation of the bacterial culture. The potency of the purified polysaccharide is assessed by molecular size and O-acetyl content. Phenol, 0.25%, is added as a preservative. The vaccine contains residual polydimethylsiloxane or fatty-acid ester-based antifoam. The vaccine is a clear, colorless solution. Each dose of 0.5 mL is formulated to contain 25 mcg of purified Vi polysaccharide in a colorless isotonic phosphate buffered saline (pH 7 ± 0.3), 4.150 mg of Sodium Chloride, 0.065 mg of Disodium Phosphate, 0.023 mg of Monosodium Phosphate, and 0.5 mL of Sterile Water for Injection. The vial stopper and the plunger stopper of the syringe are not made with natural rubber latex.

Typhoid fever is an infectious disease caused by S typhi. Humans are the only natural host and reservoir for S typhi; infections result from the consumption of food or water that has been contaminated by the excretions of an acute case or a carrier. S typhi organisms efficiently invade the human intestinal mucosae ultimately leading to bacteremia; following a typical 10- to 14-day incubation period, a systemic illness occurs. The clinical presentation of typhoid fever exhibits a broad range of severity and can be debilitating. Classical cases have fever, myalgia, anorexia, abdominal discomfort and headaches; the fever increases step-wise over a period of days and then may remain at 102°F to 106°F over 10 to 14 days before decreasing in a step-wise manner. Skin lesions known as rose spots may be present. Constipation is common in older children and adults, while diarrhea may occur in younger children. Among the less common but most severe complications are intestinal perforation and hemorrhage, and death. The course is typically more severe without appropriate antimicrobial therapy. The case fatality rate was reported to be approximately 10% to 20% in the pre-antibiotic era. (1) (2) (3) During the period of 1983 to 1991 in the US, the case fatality rate reported to the Centers for Disease Control and Prevention (CDC) was 0.2% (9/4010). (4) Infection of the gallbladder can lead to the chronic carrier state.

Typhoid fever is still endemic in many countries of the world where it is predominantly a disease of school-age children and may be a major public health problem. Most cases of typhoid fever in the US are thought to be acquired during foreign travel. During the periods of 1975 to 1984 and 1983 to 1984, respectively, 62% and 70% of the cases of typhoid fever reported to the CDC were acquired during foreign travel; this compares to 33% of cases during 1967-1972. (5)

In 1992, 414 cases of typhoid fever were reported to the CDC. Of these 414 cases, 1 (0.2%) case occurred in an infant under one year of age; 77 (18.6%) cases occurred in persons one to nine years of age; 81 (19.6%) cases occurred in persons 10 to 19 years of age; 251 (60.6%) cases occurred in individuals ≥20 years of age; the age was not available for 4 (1%) cases. One death was reported in 1991. (4) Domestic surveillance could underestimate the risk of typhoid fever in travelers since the disease is unlikely to be reported for persons who received diagnosis and treatment overseas. (6)

Approximately 2% to 4% of acute typhoid fever cases develop into a chronic carrier state. The chronic carrier state occurs more frequently with advanced age, and among females than males. (2) (7) 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 new individuals. Outbreaks of typhoid fever are often traced to food handlers who are asymptomatic carriers. (8)

Two formulations were utilized in studies of the Typhoid Vi Polysaccharide Vaccine. These included the liquid formulation which is identical to Typhim Vi vaccine and a lyophilized formulation.

The protective efficacy of each of these formulations of the Typhoid Vi Polysaccharide Vaccine was assessed independently in two trials conducted in areas where typhoid fever is endemic. A single intramuscular dose of 25 mcg was used in these efficacy studies. A randomized double-blind controlled trial with Typhim Vi vaccine (liquid formulation) was conducted in five villages west of Katmandu, Nepal. There were 6,908 vaccinated subjects: 3,454 received Typhim Vi vaccine and 3,454 in the control group received a 23-valent pneumococcal polysaccharide vaccine. Of the 6,908 subjects, 6,439 subjects were in the target population of 5 to 44 years of age. In addition, 165 children ages 2 to 4 years and 304 adults over 44 years of age were included in the study. The overall protective efficacy of Typhim Vi vaccine was 74% (95% confidence interval (CI): 49% to 87%) for blood culture confirmed cases of typhoid fever during 20 months of post-vaccination follow-up. (9) (10) (11)

The protective efficacy of the Typhoid Vi Polysaccharide Vaccine, lyophilized formulation, was evaluated in a randomized double-blind controlled trial conducted in South Africa. There were 11,384 vaccinated children 5 to 15 years of age; 5,692 children received the Vi capsular polysaccharide vaccine and 5,692 in the control group received Meningococcal Polysaccharide (Groups A+C) Vaccine. The protective efficacy for the Vi capsular polysaccharide (lyophilized formulation) group for blood culture confirmed cases of typhoid fever was 55% (95% CI: 30% to 70%) overall during 3 years of post-vaccination follow-up, and was 61%, 52% and 50%, respectively, for years 1, 2, and 3. Vaccination was associated with an increase in anti-Vi antibodies as measured by radioimmunoassay (RIA) and enzyme-linked immunosorbent assay. Antibody levels remained elevated at 6 and 12 months post-vaccination. (11) (12)

Because of the low incidence of typhoid fever, efficacy studies were not feasible in a US population.

Controlled comparative efficacy studies of Typhim Vi vaccine and other types of typhoid vaccines have not been performed.

An increase in serum anti-capsular antibodies is thought to be the basis of protection provided by Typhim Vi vaccine. However, a specific correlation of post-vaccination antibody levels with subsequent protection is not available, and the level of Vi antibody that will provide protection has not been determined. Also, limitations exist for comparing immunogenicity results from subjects in endemic areas, where some subjects have baseline serological evidence of prior S typhi exposure, to naive populations such as most American travelers.

In endemic regions (Nepal, South Africa, Indonesia) where trials were conducted, pre-vaccination geometric mean antibody levels suggest that infection with S typhi had previously occurred in a large percentage of the vaccinees. In these populations, specific antibody levels increased four-fold or greater in 68% to 87.5% of older children and adult subjects following vaccination. For 43 persons 15 to 44 years of age in the Nepal pilot study, geometric mean specific antibody levels pre- and 3 weeks post-vaccination were, respectively, 0.38 and 3.68 mcg antibody/mL by RIA; 79% had a four-fold or greater rise in Vi antibody levels. (9) (12)

Immunogenicity and safety trials were conducted in an adult US population. A single dose of Typhim Vi vaccine induced a four-fold or greater increase in antibody levels in 88% and 96% of this adult population for 2 studies, respectively, following vaccination (see Table 1). (10) (13)

No studies of safety and immunogenicity have been conducted in US children. A double-blind randomized controlled trial evaluating the safety and immunogenicity of Typhim Vi vaccine was performed in 175 Indonesian children. The percentage of 2- to 5-year-old children achieving a four-fold or greater increase in antibody levels at 4 weeks post-vaccination was 96.3% (52/54) (95% CI: 87.3% to 99.6%), and in the study subset of 2-year-old children was 94.4% (17/18) (95% CI: 72.7% to 99.9%). The geometric mean antibody levels (mcg antibody/mL by RIA) for the 2- to 5-year-old children and the subset of 2-year-olds were, respectively, 5.81 (4.36 to 7.77) and 5.76 (3.48 to 9.53). (10) (11)

In the US Reimmunization Study, adults previously immunized with Typhim Vi vaccine in other studies were reimmunized with a 25 mcg dose at 27 or 34 months after the primary dose. Data on antibody response to primary immunization, decline following primary immunization, and response to reimmunization are presented in Table 2. Antibody levels attained following reimmunization at 27 or 34 months after the primary dose were similar to levels attained following the primary immunization. (10) (13) This response is typical for a T-cell independent polysaccharide vaccine in that reimmunization does not elicit higher antibody levels than primary immunization. The safety of reimmunization was also evaluated in this study (see ADVERSE REACTIONS section).

Typhim Vi vaccine is indicated for active immunization for the prevention of typhoid fever caused by S typhi and is approved for use in persons two years of age or older.

Immunization with Typhim Vi vaccine should occur at least two weeks prior to expected exposure to S typhi.

Typhim Vi vaccine is not indicated for routine immunization of individuals in the United States (US). (14)

Selective immunization against typhoid fever is recommended under the following circumstances: 1) travelers to areas where a recognized risk of exposure to typhoid exists, particularly ones who will have prolonged exposure to potentially contaminated food and water, 2) persons with intimate exposure (ie, continued household contact) to a documented typhoid carrier, and 3) workers in microbiology laboratories who frequently work with S typhi. (14)

Typhoid vaccination is not required for international travel, but is recommended for travelers to such areas as Africa, Asia, and Central and South America where there is a recognized risk of exposure to S typhi. Current CDC advisories should be consulted with regard to specific locales. Vaccination is particularly recommended for travelers who will have prolonged exposure to potentially contaminated food and water. However, even travelers who have been vaccinated should use caution in selecting food and water. (15)

There is no evidence to support the use of typhoid vaccine to control common source outbreaks, disease following natural disaster or in persons attending rural summer camps. (14)

An optimal reimmunization schedule has not been established. Reimmunization every two years under conditions of repeated or continued exposure to the S typhi organism is recommended at this time.

For recommended primary immunization and reimmunization see DOSAGE AND ADMINISTRATION section.

Typhim Vi vaccine should not be used to treat a patient with typhoid fever or a chronic typhoid carrier.

Typhim Vi vaccine is contraindicated in patients with a history of hypersensitivity to any component of this vaccine.

Allergic reactions have been reported rarely in the post-marketing experience (see ADVERSE REACTIONS section).

The safety and immunogenicity of Typhim Vi vaccine in children under two years of age has not been established. As with other polysaccharide vaccines, the antibody response may be inadequate. The decision whether to vaccinate children under 2 years of age depends upon the risk incurred by the child on the basis of the epidemiological context.

Typhim Vi vaccine provides protection against the risk of infection related to Salmonella typhi, but gives no protection against Salmonella paratyphi A or B, non-S typhi species of Salmonella enterica serovar Typhi, or other bacteria that cause enteric disease.

If the vaccine is used in persons deficient in producing antibodies, whether due to genetic defect, immunodeficiency disease, or immunosuppressive therapy, the expected immune response may not be obtained. This includes patients with asymptomatic or symptomatic HIV-infection, severe combined immunodeficiency, hypogammaglobulinemia, or agammaglobulinemia; altered immune states due to diseases such as leukemia, lymphoma, or generalized malignancy; or an immune system compromised by treatment with corticosteroids, alkylating drugs, antimetabolites or radiation. (16)

As with any vaccine, vaccination with Typhim Vi vaccine may not protect 100% of individuals.

Adverse event information is derived from clinical trials and worldwide post-marketing experience.

For intramuscular use only.

Preparation for Administration

The syringe or vial and its packaging should be inspected prior to use for evidence of leakage, premature activation of the plunger, or a faulty tip seal. If any of these conditions exists, do NOT administer the vaccine.

• Syringe

Picture A: Luer-Lok™ syringe

Step 1: Holding the syringe cap in one hand (avoid holding the syringe plunger or barrel), unscrew the tip cap by twisting it counterclockwise.
Step 2: To attach the needle to the syringe, gently twist the needle clockwise into the syringe until slight resistance is felt.

The syringe is intended for single use only, must not be reused, and must be disposed of properly and promptly following its use.

• Vial

Tear off upper seal of vial cap. Cleanse top of rubber stopper of the vial with a suitable antiseptic.

Use a separate sterile syringe and needle or a sterile disposable unit for each individual patient to prevent the transmission of infectious agents from person to person. Needles should not be recapped and should be properly disposed.

Single-dose syringe, without needle, 0.5 mL, NDC 49281-790-88. Packaged as NDC 49281-790-51.

Multi-dose vial, 20 Dose, NDC 49281-790-38. Packaged as NDC 49281-790-20.

1

Levine MM, et al. New knowledge on pathogenesis of bacterial enteric infections as applied to vaccine development. Microbiol. Rev. 47: 510-550, 1983

2

Levine MM. Typhoid Fever Vaccines. p 333-361. In Vaccines, Plotkin SA, Mortimer EA, eds. W.B. Saunders, 1988

3

Levine MM, et al. Typhoid Fever Chapter 5, In: Vaccines and Immunotherapy. Stanley J. Cryz, Jr., Editor. pp 59-72, 1991

4

CDC. Summary of Notifiable Diseases, United States 1992. MMWR 41: No. 55, 1993

5

Ryan CA, et al. Salmonella typhi infections in the United States, 1975-1984: Increasing Role of Foreign Travel. Rev Infect Dis 11:1-8, 1989

6

Woodruff BA, et al. A new look at typhoid vaccination. Information for the practicing physician. JAMA 265: 756-759, 1991

7

Ames WR, et al. Age and sex as factors in the development of the typhoid carrier state, and a method for estimating carrier prevalence. Am J Public Health 33: 221-230, 1943

8

CDC. Typhoid fever - Skagit County, Washington. MMWR 39: 749-751, 1990

9

Acharya IL, et al. Prevention of typhoid fever in Nepal with the Vi capsular polysaccharide of Salmonella typhi. N Engl J Med 317: 1101-1104, 1987

10

Unpublished data available from Sanofi Pasteur Inc., compiled 1991

11

Unpublished data available from Sanofi Pasteur SA

12

Klugman KP, et al. Protective activity of Vi capsular polysaccharide vaccine against typhoid fever. The Lancet, 1165-1169, 1987

13

Keitel WA, et al. Clinical and serological responses following primary and booster immunization with Salmonella typhi Vi capsular polysaccharide vaccines. Vaccines 12: 195-199, 1994

14

Recommendations of the Immunization Practices Advisory Committee (ACIP). Typhoid Immunization. MMWR 43: No. RR-14, 1994

15

CDC. Health Information for International Travel 2001-2002. Atlanta: US Department of Health and Human Services, Public Health Service, 2001

16

ACIP: Use of vaccines and immune globulins in persons with altered immunocompetence. MMWR 42: No. RR-4, 1993

17

CDC. Vaccine Adverse Event Reporting System - United States. MMWR 39: 730-733, 1990

18

ACIP: Update on Adult Immunization. MMWR 40: No. RR-12, 1991

Product Information as of March 2020.

Manufactured by:
Sanofi Pasteur SA
Lyon, France
US Govt License #1724

Distributed by:
Sanofi Pasteur Inc.
Swiftwater, PA 18370 USA
1-800-VACCINE (1-800-822-2463)

NDC 49281-790-88

Typh
Typhoid Vi
Polysaccharide
Vaccine
Typhim Vi®

single-dose
(0.5 mL)

IM only
Rx only

Sanofi Pasteur

NDC 49281-790-51

Typhoid Vi Polysaccharide Vaccine
Typhim Vi®

Single-dose prefilled syringe

FOR INTRAMUSCULAR ADMINISTRATION.

For indications and directions see enclosed package circular.

Typh

single-dose
prefilled syringe
(0.5 mL)

Rx only

SANOFI PASTEUR

NDC 49281-790-38

Typhoid Vi
Polysaccharide
Vaccine – Typhim Vi®

Typh

multi-dose
vial
(20 doses)

IM only
For indications and directions see
enclosed package insert.
Store at 2° to 8°C (35° to 46°F).

DO NOT FREEZE. DISCARD IF FROZEN.

Rx only

US Govt License #1724
Manufactured by:
Sanofi Pasteur SA
Lyon France

Distributed by:
Sanofi Pasteur Inc.
Swiftwater, PA 18370 USA
1-800-VACCINE (1-800-822-2463)

Sanofi Pasteur

NDC 49281-790-20

Typhoid Vi
Polysaccharide Vaccine
Typhim Vi®

Typh

multi-
dose vial
(20 doses)

Rx only

SANOFI PASTEUR