These revised recommendations of the Advisory Committee on Immunization Practices
update recommendations published in MMWR in 1994 (1) and include updated information
on the two currently available vaccines and on vaccine safety. They also include an
update on the epidemiology of enteric fever in the United States, focusing on increasing
drug resistance in Salmonella enterica serotype Typhi, the cause of typhoid fever,
as well as the emergence of Salmonella serotype Paratyphi A, a cause of paratyphoid
fever, against which typhoid vaccines offer little or no protection.
Introduction
Salmonella enterica serotypes Typhi and Paratyphi A, Paratyphi B (tartrate negative),
and Paratyphi C cause a protracted bacteremic illness referred to respectively as
typhoid and paratyphoid fever, and collectively as enteric fever. Enteric fever can
be severe and even life-threatening. It is most commonly acquired from water or food
contaminated by the feces of an infected person. The incubation period is 6–30 days,
and illness onset is insidious, with gradually increasing fatigue and fever. Malaise,
headache, and anorexia are nearly universal. A transient macular rash can occur. When
serious complications (e.g., intestinal hemorrhage or perforation) occur, it is generally
after 2–3 weeks of illness. Untreated illness can last a month (2). Patients with
untreated typhoid fever were reported to have case-fatality rates >10% (3); the overall
case-fatality rate with early and appropriate antibiotic treatment is typically <1%
(4).
Recommendations for routine use of vaccines in children, adolescents, and adults are
developed by the Advisory Committee on Immunization Practices (ACIP). ACIP is chartered
as a federal advisory committee to provide expert external advice and guidance to
the Director of the Centers for Disease Control and Prevention (CDC) on use of vaccines
and related agents for the control of vaccine-preventable diseases in the civilian
population of the United States. Recommendations for routine use of vaccines in children
and adolescents are harmonized to the greatest extent possible with recommendations
made by the American Academy of Pediatrics (AAP), the American Academy of Family Physicians
(AAFP), and the American College of Obstetricians and Gynecologists (ACOG). Recommendations
for routine use of vaccines in adults are harmonized with recommendations of AAFP,
ACOG, and the American College of Physicians (ACP). ACIP recommendations approved
by the CDC Director become agency guidelines on the date published in the Morbidity
and Mortality Weekly Report (MMWR). Additional information is available at http://www.cdc.gov/vaccines/acip.
Typhoid fever is uncommon in the United States, with an average of about 400 cases
reported annually during 2007–2011 (5). Approximately 90% of U.S. cases occur among
persons returning from foreign travel, and >75% of travelers had been in India, Bangladesh,
or Pakistan (5). Most travelers (≥55%) reported that their reason for travel was visiting
friends or relatives (5). Even short-term travel to high-incidence areas is associated
with risk for typhoid fever (6). CDC recommends typhoid vaccination for travelers
to many Asian, African, and Latin American countries, but, as of 2010, no longer recommends
typhoid vaccine for travelers to certain Eastern European and Asian countries (7);
the most recent pre-travel vaccination guidelines are available at http://wwwnc.cdc.gov/travel.
The importance of vaccination and other preventive measures for typhoid fever is heightened
by increasing resistance of Salmonella serotype Typhi to antimicrobial agents, including
fluoroquinolones, in many parts of the world (8).
Paratyphoid fever, caused primarily by Salmonella enterica serotype Paratyphi A, but
also by serotypes Paratyphi B (tartrate negative) and C, is an illness clinically
indistinguishable from typhoid fever (9). Serotype Paratyphi A is responsible for
a growing proportion of enteric fever cases in many countries, accounting for as much
as half of the cases (8). Neither typhoid vaccine available in the United States is
licensed by the Food and Drug Administration for prevention of paratyphoid fever,
although limited observational data suggest the oral, live-attenuated Ty21a vaccine
might offer some protection against Paratyphi B (tartrate negative) (10).
Typhoid Vaccines
Two typhoid vaccines are available for use in the United States: 1) a Vi capsular
polysaccharide vaccine for parenteral use (Typhim Vi, manufactured by Sanofi Pasteur)
and 2) an oral live-attenuated vaccine (Vivotif, manufactured from the Ty21a strain
of Salmonella serotype Typhi by PaxVax). A parenteral heat-phenol-inactivated whole-cell
vaccine first licensed by Wyeth in 1952 and associated with high rates of fever and
systemic reactions was discontinued in 2000 (6).
No efficacy studies among travelers from nonendemic areas are available for either
vaccine, though a Ty21a vaccine challenge study among North American volunteers demonstrated
significant protection from disease (11,12). The two currently available vaccines
have moderate efficacy in populations where typhoid is endemic. In a systematic review
and meta-analysis, the estimated 2.5–3.0 year cumulative efficacy was 55% (95% confidence
interval [CI] = 30%–70%) for the parenteral Vi polysaccharide vaccine and 48% (CI
= 34%–58%) for the oral Ty21a vaccine, each based on a single trial (13). A trial
in Kolkata, India, of the Vi polysaccharide vaccine found a protective effectiveness
of 61% (CI = 41%–75%) among all participants (14). Studies conflict regarding the
effectiveness of the Vi vaccine in young children. The trial in Kolkata, which included
adults as well as children, found 80% (CI = 53%–91%) effectiveness among those 2–4
years (14), whereas a trial in Karachi, Pakistan, which included only children 2–16
years, showed no protection among children 2–4 years (15). Herd effects might have
contributed to the high effectiveness observed among young children in the Kolkata
trial. An observational study of the effectiveness of typhoid vaccination in U.S.
travelers estimated 80% protection; however, this study addressed typhoid vaccination
in general, not specific vaccines (16).
Protein-conjugated Vi polysaccharide vaccines have been shown to have high efficacy
in young children (17) and have been licensed in other countries (18), but are not
currently licensed or available in the United States.
Vaccine Usage
Routine typhoid vaccination is not recommended in the United States.
Vaccination is recommended for the following groups:
Travelers to areas where there is a recognized risk for exposure to Salmonella serotype
Typhi (the most recent guidelines are available at http://wwwnc.cdc.gov/travel). Risk
is greatest for travelers who have prolonged exposure to possibly contaminated foods
and beverages, although short-term travelers are also at risk (6). Most travel-associated
typhoid fever cases in the United States occur among travelers who are visiting friends
or relatives; many travelers in this group do not seek pre-travel health care (19).
Multidrug-resistant strains of Salmonella serotype Typhi have become common in many
regions (8), and cases of typhoid fever that are treated with drugs to which the organism
is resistant can be fatal. Travelers should be cautioned that typhoid vaccination
is not a substitute for careful selection of food and beverages. Typhoid vaccines
are not 100% effective, and vaccine-induced protection can be overwhelmed by large
inocula of Salmonella serotype Typhi.
Persons with intimate exposure (e.g., household contact) to a documented Salmonella
serotype Typhi chronic carrier (defined as excretion of Salmonella serotype Typhi
in urine or stool for >1 year).
Microbiologists and other laboratory workers routinely exposed to cultures of Salmonella
serotype Typhi or specimens containing this organism or who work in laboratory environments
where these cultures or specimens are routinely handled.
Choice of Vaccine
Parenteral Vi polysaccharide and oral Ty21a are both acceptable forms of typhoid vaccine.
The Vi polysaccharide vaccine is administered as a single injection and is approved
for adults and children aged ≥2 years. The oral Ty21a vaccine is administered in 4
doses on alternating days over 1 week and is approved for adults and children aged
≥6 years. Immunocompromised persons should not use Ty21a because it is a live-attenuated
vaccine. Because antibacterial drugs might be active against the vaccine strain and
reduce immunogenicity, the Ty21a vaccine should not be administered to persons taking
these medications.
Vaccine Administration
Vi polysaccharide
Primary vaccination with Vi polysaccharide consists of one 0.5-mL (25-μg) dose administered
intramuscularly. This vaccine should be given at least 2 weeks before potential exposure.
Ty21a
Primary vaccination with live-attenuated Ty21a vaccine consists of one enteric-coated
capsule taken on alternate days (day 0, 2, 4, and 6), for a total of four capsules.
The capsules must be kept refrigerated (not frozen). Each capsule should be taken
with cool water no warmer than 98.6°F (37.0°C), approximately 1 hour before a meal.
All doses should be completed at least 1 week before potential exposure.
Repeat Doses
If continued or repeated exposure to Salmonella serotype Typhi is expected, repeat
doses of typhoid vaccine are needed to maintain immunity (Table). An optimal revaccination
schedule for the Vi polysaccharide vaccine has not been established; however, the
manufacturer recommends a repeat dose every 2 years after the primary dose if continued
or renewed exposure is expected (20). The manufacturer of Ty21a recommends revaccination
with the entire 4-dose series every 5 years if continued or renewed exposure to Salmonella
serotype Typhi is expected (21).
Adverse Reactions
Evidence from trials and postmarketing studies suggest that parenteral Vi vaccines
are usually tolerated well (20). In field trials, pain (risk ratio [RR] = 8.0; CI
= 3.7–17.2) and swelling at the injection site (RR = 6.0; CI = 1.1–34.2) were more
common among vaccinees than placebo recipients, but no significant difference was
found in the incidence of fever or erythema (13). In a manufacturer-funded postmarketing
safety study conducted in 11 U.S. travel clinics, the most common reactions were injection
site pain (77%), tenderness (75%), and muscle aches (39%) (22). In postmarketing surveillance
of the Vi vaccine (administered alone or simultaneously with other vaccines) during
1995–2002, an estimated 0.3 serious events* per 100,000 doses distributed were reported
to the U.S. Vaccine Adverse Events Reporting System (VAERS) (23). Among the 321 VAERS
reports of events occurring after Vi vaccination, the most commonly reported symptoms
included injection site reactions, fever, headache, rash, urticaria, abdominal pain,
and nausea. It is important to note that adverse events reported to VAERS might not
be caused by the vaccine.
In a meta-analysis of Ty21a vaccine placebo-controlled trials, fever was more common
among vaccinees (RR = 1.8; CI = 1.0–3.1), but other adverse events occurred with equal
frequency among groups receiving vaccine and placebo; risk for any mild adverse event
was higher among vaccinees (RR = 1.7; CI = 1.0–2.7) (13). In a combined analysis of
data from a pilot study and a field trial, fewer than 10% of vaccinees reported abdominal
pain (6.4%), nausea (5.8%), headache (4.8%), fever (3.3%), diarrhea (2.9%), vomiting
(1.5%), or skin rash (1.0%) (21,24,25). One nonfatal case of anaphylactic shock, which
was considered to be an allergic reaction to the vaccine, was reported to the manufacturer
(21). In VAERS postmarketing surveillance of the Ty21a vaccine (administered alone
or simultaneously with other vaccines) during 1991–2002, an estimated 0.6 serious
events per 100,000 doses distributed were reported (23). Among the 345 reports of
events occurring after Ty21a vaccination, the most commonly reported symptoms included
diarrhea, nausea, fever, abdominal pain, headache, rash, vomiting, and urticaria (23).
Precautions and Contraindications
No data have been reported on the use of either typhoid vaccine in pregnant women.
In general, live vaccines like Ty21a are contraindicated in pregnancy (26). Vi polysaccharide
vaccine should be given to pregnant women only if clearly needed (20).
Because Ty21a is a live-attenuated vaccine, antimicrobial agents might interfere with
vaccine activity. To be sure the vaccine is fully effective, the vaccine manufacturer
advises that Ty21a should not be given until at least 3 days after the last dose of
antimicrobial agent and, if possible, antimicrobial agents should not be started within
3 days of the last dose of Ty21a vaccine (27). A longer interval should be considered
for long-acting antimicrobials (e.g., azithromycin). The antimalarial agents mefloquine
and chloroquine and the combinations atovaquone/proguanil and pyrimethamine/sulfadoxine
can, at doses used for prophylaxis, be administered together with the Ty21a vaccine;
however, the manufacturer advises that other antimalarial agents only be administered
at least 3 days after the last vaccine dose (27). Ty21a vaccine can be administered
simultaneously or at any interval before or after other live vaccines (injectable
or intranasal) or immune globulin if indicated (26). Ty21a should not be administered
to persons during an acute febrile illness or acute gastroenteritis (21).
Live-attenuated Ty21a vaccine should not be used by immunocompromised persons. The
Vi vaccine is theoretically safer for this group. Although the Ty21a strain can be
shed in the stool of vaccinees, transmission has not been documented (21). The Ty21a
strain has not been isolated from blood cultures after vaccination (21). Both the
Vi polysaccharide and Ty21a vaccines are contraindicated in patients with a history
of hypersensitivity to any component of the vaccine.
What is currently recommended?
In 1994, Advisory Committee on Immunization Practices (ACIP) approved recommendations
for typhoid vaccination, stating that typhoid vaccine is indicated for U.S. travelers
to certain countries, close contacts of chronic carriers, and certain laboratory workers.
Since 1994, the parenteral heat-phenol-inactivated whole-cell vaccine has been discontinued.
Why are the recommendations being modified now?
The updated recommendations contain new data on the epidemiology of typhoid fever
and vaccine effectiveness and safety. No substantive changes have been made to ACIP
typhoid vaccine recommendations apart from removing the discontinued parenteral whole-cell
vaccine from the list of available typhoid vaccines. The two typhoid vaccines available
in the United States are parenteral Vi capsular polysaccharide vaccine and oral live-attenuated
Ty21a vaccine.
What are the new recommendations?
Typhoid vaccine continues to be recommended for U.S. travelers to certain countries
(the most recent guidelines are available at http://wwwnc.cdc.gov/travel), close contacts
of chronic carriers, and certain laboratory workers.