Commercializing diarrhea vaccines for travelers

Abstract

Continued growth in international travel and forecasts for a great increase in the number of people who travel from industrialized to emerging and developing countries make it necessary to develop and improve the capacity to provide health protection to travelers. Measures available to prevent some diseases include a currently limited number of marketed vaccines which represent extremely useful tools to protect travelers. Travelers very often experience diarrheal and gastrointestinal diseases for which some vaccines are available. Use of these vaccines should be evaluated based on traveler and travel destination and characteristics. Vaccines available include those against cholera, typhoid fever, hepatitis A, hepatitis E (only available in China), and rotavirus. The aim of this review is to provide an updated summary about each of the abovementioned vaccines that may be useful for making decisions regarding their use and assessing their indications in recommendations for travelers.

Keywords: :

• cholera
• commercializing vaccines
• hepatitis A
• hepatitis E
• rotavirus
• traveler’s diarrhea
• typhoid fever
• vaccines

Introduction

International travel has continuously increased over the past 6 decades. Today, the number of arrivals of international tourists worldwide is approximately 1000 million, and will increase on average 3.3% annually during the 2010–2030 period. In addition, this is an emerging economic activity. Although a great part of this travel occurs between industrialized countries with modern health infrastructures and systems, travel to Asia and the Pacific, followed by Africa and America, has experienced the greatest increase in recent years.¹ These geographic areas have widely diverse health situations as regards risk of disease for travelers, with great differences within each country and particularly between rural and urban areas. Internationally available vaccines to prevent disease in travelers, and specifically the most common conditions, including gastrointestinal and diarrheal diseases, vary over time. This study was therefore aimed at providing an update that allows for reviewing the vaccines against these traveler diseases marketed worldwide.

More than 1400 species of infectious agents have been reported to cause disease in humans. These include more than 300 pathogenic diseases of sustained clinical importance. Among these, there are about 100 diseases that pose a threat to non-immune travelers. Some of these clinically significant diseases may be prevented by vaccination, which is performed as routine childhood immunization for only 19 of them.²

Gastroenteric diseases are most common among people traveling from industrialized to less developed countries. Most of the gastrointestinal disease outbreaks have been linked to food or water consumed.

Diarrhea is usually a symptom of an intestinal tract infection, which may be caused by a variety of bacterial, viral, and parasitic organisms and occurs worldwide. The WHO defines diarrhea as the passage of 3 or more loose or liquid stools daily (or more frequent passage than is normal for the individual). Infection is spread through contaminated food or drinking water, or from person-to-person as a result of poor hygiene. Water contaminated with human feces, for example from municipal sewage, septic tanks and latrines, is of special concern. Animal feces also contain microorganisms that may cause diarrhea. Food is another major cause of diarrhea when it is prepared or stored in unhygienic conditions. Water can contaminate food during irrigation, and fish and seafood from polluted water may also contribute to the disease. Rotavirus and Escherichia coli currently are the 2 most common etiological agents of diarrhea in developing countries.

Diarrhea due to infection may last a few days, or several weeks, as occurs in persistent diarrhea. Severe diarrhea may be life-threatening due to fluid loss in watery diarrhea, particularly in infants and young children, malnourished people, and those with impaired immunity. Diarrhea is also associated with other infections such as malaria and measles. Chemical irritation of the gut or non-infectious bowel disease may also result in diarrhea.

The infectious agents causing diarrhea are present or are sporadically introduced worldwide. Diarrhea is a rare occurrence in most people living in developed countries where sanitation is widely available, access to safe water is high, and personal and domestic hygiene is relatively good. Currently available data suggest that approximately 768 million people have no access to improved water sources, 2.5 billion have no basic sanitation, and 1 billion people practice open defecation.³

Globally, diarrheal disease is the second leading cause of death in children under 5 y of age. There are every year nearly 1.7 billion cases of diarrheal disease, which kills approximately 760 000 children under 5 y of age.³ A very significant proportion of these may be prevented through safe drinking water and adequate sanitation and hygiene.

The main infectious diseases to which travelers may be exposed are foodborne and waterborne diseases. These have a sufficiently high global or regional prevalence to represent a significant risk for travelers, and some of them are diseases that involve a risk to public health due to transmission of infection to others by the infected traveler.⁴ The most common infectious illness affecting travelers is “traveler’s diarrhea” (TD), which may be caused by many different foodborne and waterborne infectious agents and for which treatment and precautions are essentially the same. The most common source of traveler exposure to disease-causing organisms is intake of contaminated drinking water and food. It is estimated that 80% of TD cases are caused by bacterial pathogens (E. coli, Shigella, Salmonella, Campylobacter, Vibrio cholerae…). Other pathogens include viruses (hepatitis A and E, rotaviruses, caliciviruses - the noroviruses responsible for most gastroenteritis winter outbreaks in industrialized countries-) and protozoa (Giardia lamblia, Cryptosporidium parvum, Entamoebahistolytica, and Cyclospora).^5,6 Diarrheas may also be caused by other bacterial pathogens such as Staphylococcus aureus, Clostridium perfringens, Clostridium difficile, or Klebsiella.⁷ In addition, mild cases of cholera, caused by Vibrio cholerae, are often indistinguishable from other causes of acute diarrheal disease. The increased frequency of antibacterial drug resistance among these pathogens is a source of major concern.

Depending on travel destination, travelers may be exposed to a number of infectious diseases; exposure depends on the presence of infectious agents in the area to be visited. The risk of infection will vary depending on the purpose of the trip and the itinerary within the area, the accommodation, hygiene and sanitation standards, and the behavior of the traveler.⁴

Key measures to prevent gastrointestinal diseases usually include access to safe drinking water, use of improved sanitation, hand washing with soap, health education about how infections spread, and vaccination (only for some pathogens: including cholera/ETEC, typhoid fever, hepatitis A/E and/or rotavirus).

People with weakened immune systems, pregnant women, and infants are groups especially at risk for foodborne and waterborne diseases. Travelers who fall into these groups should make a special effort to keep strictly to the recommendations for consuming safe water and food.

It was traditionally thought that traveler’s diarrhea could be prevented by following simple recommendations such as “boil it, cook it, peel it, or forget it,” but studies have found that people who follow these rules may still become ill. Poor hygiene in local restaurants is probably the largest contributor to the risk of TD. Although food and water precautions continue to be recommended, travelers may not always be able to follow the advice. Moreover, many of the factors that ensure food safety, such as restaurant hygiene, are out of traveler’s control.⁸

Prophylactic antibiotics should not currently be recommended for most travelers in order to prevent diarrheal disease. Prophylactic antibiotics afford no protection against nonbacterial pathogens and may remove normally protective microflora from the bowel, rendering travelers more susceptible to infection with resistant bacterial pathogens. In addition, use of antibiotics may be associated with allergic or adverse reactions in a certain proportion of travelers and may potentially contribute to drug resistance. Prophylactic antibiotics may be considered for short-term travelers who are high-risk hosts (such as those who are immunosuppressed) or who are making critical trips during which even a short bout of diarrhea could affect the trip.⁸

Travelers have available a limited number of vaccines for preventing foodborne diseases. Different vaccines against cholera, typhoid fever, hepatitis A, hepatitis E, and rotavirus are currently authorized and marketed in many countries worldwide, but not all of them are indicated for all age groups. Polyomyelitis, which is about to be eradicated, is considered as an exception and will not be discussed in this article because, although it enters the body through the gastrointestinal tract, its clinical signs are essentially neurological in nature and vaccination against it is universal. Adequate vaccination of travelers must therefore be verified, particularly if they travel to countries where risk of transmission still exists.

Each of the abovementioned vaccines recommended for travelers in order to prevent or decrease the risks of gastrointestinal and/or diarrheal diseases are described below.

Cholera

Cholera is an acute diarrheal illness of variable severity caused by intestinal infection with the bacterium Vibrio cholerae (serogroups O1 and O139). Every year, there are an estimated 3–5 million cases of cholera and 100 000–120 000 deaths from cholera.⁹ The incubation period is very short (2 h to 5 d), and the condition may kill within hours. The infectious agent produces an enterotoxin that causes copious, painless, watery diarrhea that may quickly lead to severe dehydration and death if treatment is not promptly given. Vomiting also occurs in most patients.

Approximately 75% of people infected with cholera develop no symptoms; when illness occurs, about 80–90% of episodes are mild or moderate in nature and are difficult to distinguish clinically from other types of acute diarrhea. Less than 20% of ill people develop typical cholera with signs of moderate or severe dehydration.

Only the O1 and O139 serogroups cause epidemic disease. All other strains are called non-O1 non-O139 V. cholerae and cause no cholera symptoms. Serogroups O5, O37, and O141 can cause small outbreaks of diarrheal disease, but usually no epidemics. V. cholerae O1 causes the majority of outbreaks, while O139 – first identified in Bangladesh in 1992 – is confined to South East Asia.⁹ In 2012, only China has reported cases caused by O139 strains, so that 52 out of the 69 confirmed cases in this country were due to this serogroup.¹⁰ In recent years, new variant strains have been detected in several parts of Asia and Africa, and have been reported to be associated to greater clinical severity.

When V. cholerae is ingested with food or water, steps in pathogenicity of cholera include colonization of small intestinal mucosa, production of the pilus structure, and elaboration of the enterotoxin cholera toxin (CT, a central active A subunit bound to 5 surrounding B subunits). The B subunit is responsible for toxin binding to the GM1 ganglioside receptors on the epithelial cell surface, whereas the A subunit, an ADP-ribosylating enzyme, is responsible for toxin toxicity through stimulation of the target cell adenylate cyclase, leading to hypersecretion of fluids and loss of electrolytes. Immunity to V. cholerae infection is serogroup-specific, so that immunity to O1 does not protect from infection with serogroup O139.¹¹

People with certain factors may have an increased susceptibility to the disease. Thus, individuals with reduced stomach acid or hypochlorhydria, type O blood, compromised immunity, and traveling from more developed areas to countries with deficient drinking water supply and improper handling of food are likely to develop cholera if they do not take preventive measures. Risk of cholera was 1 to 2 cases per million travelers, but according to recent estimates, it could be as high as 5 per 1000 for travelers who visit countries where a cholera outbreak is occurring.

Cholera is still a global threat, and is one of the key indicators of social development. While the disease no longer poses a threat to countries with minimum standards of hygiene, it remains a challenge to countries where access to safe drinking water and adequate sanitation cannot be guaranteed. In 2012, a total of 48 countries from all continents reported cholera cases to the WHO, which represents a 17% decrease in the number of countries as compared with 2011. In this year, the 64th World Health Assembly stated that re-emergence of cholera was a significant public health burden and called for implementation of an integrated and comprehensive approach to cholera control which may include use of oral cholera vaccines.

Two oral cholera vaccines are currently marketed internationally (Dukoral® and Shanchol®), and both have been developed and proved to be safe, immunogenic, and effective. Based on recent data about the effectiveness, feasibility, and cost-effectiveness of oral cholera vaccination, recommendations are that the 2 oral cholera vaccines should be used in areas with endemic cholera and should be considered for use in areas at risk for cholera outbreaks, in conjunction with other cholera prevention and control strategies.

The WC/rBS (whole cell/recombinant B subunit) vaccine, Dukoral^®, licensed by Crucell/Johnson and Johnson and available in several countries, consists of 4 batches of heat- or formalin-killed whole cell V. cholerae O1, representing both serotypes (Inaba and Ogawa) and both biotypes (classical and El Tor), to which purified recombinant CT subunit B (CTB) is added. The B subunit of cholera toxin was originally produced chemically (WC-BS), but is now produced by recombinant technology (WC-rBS). The whole cell/recombinant B subunit (WC/rBS) vaccine is given orally with buffer to neutralize stomach acidity and confers 85–90% protection during 6 mo in all age groups after administration of 2 doses 1–2 wk apart. The protective antibodies last for 2 y in 60% of the vaccinees (children older than 6 y and adults). Recent reviews of the study in Bangladesh show that efficacy of WC/rBS is boosted by herd protection. Dukoral^® is available in over 60 countries and has been pre-qualified by WHO. It is primarily used as a vaccine for travelers to cholera-endemic areas.^12,13 The vaccine also provides short-term protection against ETEC (enterotoxigenic E. coli), which is of added benefit for travelers. This is because CTB is structurally and functionally similar to the heat-labile toxin of ETEC, and the 2 toxins cross-react immunologically. Therefore, vaccines stimulating anti-heat-labile toxin immunity should provide some protection against ETEC infections. In some developed countries, it is recommended to travelers for prevention of cholera and ETEC. The effectiveness of the oral cholera vaccine (WC/rBS) in the prevention of traveler’s diarrhea has been evaluated: This vaccine could prevent traveler diarrhea in 2 out of 7 travelers.¹⁴

Primary immunization for adults and children aged ≥6 y consists of 2 oral doses given more than 7 d apart, but less than 6 wk apart; children aged 2–5 y should receive 3 doses >7 d apart, but <6 wk apart. Food and drink intake should be avoided for 1 h before and after vaccination. If the interval between primary immunization doses is >6 wk, primary immunization should be restarted. Protection is effective 1 wk after the last scheduled dose. In the event of a continued risk of V. cholerae infection, a booster dose is recommended by the manufacturer after 2 y for adults and children aged ≥6 y. If the interval between the primary series and booster immunization is >2y, primary immunization must be repeated. For children aged 2–5 y a booster dose is recommended every 6 mo. Dukoral® is not licensed for children aged <2 y.

Shanchol® and mORCVAX®: The closely related bivalent oral cholera vaccines Shanchol® and mORCVAX® are based on serogroups O1 and O139. Unlike Dukoral, these vaccines do not contain the bacterial toxin B subunit and will therefore not protect against ETEC.

The original ORCVAX was licensed in Vietnam in 1997. The vaccine was subsequently improved and licensed in 2009 as mORCVAX® in Vietnam and as Shanchol^® (Shantha Biotechnics Ltd.) in India. It is administered as 2 doses, 15 d apart, for individuals aged ≥1 y, and a booster dose is recommended after 2 y. A field trial conducted in Nha-Trang, Vietnam, showed a 66% efficacy against V. cholerae El Tor after 8 mo in all age groups tested. Its advantages include that it is bivalent (offers protection against both serogroups), does not require a buffer due to the lack of the B subunit, and is inexpensive. This new vaccine, Shanchol®, has been pre-qualified by the WHO and used together with Dukoral^® in cholera-affected countries. In logistic terms, Shanchol® and mORCVAX® require less storage space as compared with Dukoral®, and the omission of the B subunit makes Shanchol® and mORCVAX® less expensive to produce.

These vaccines have opened up the possibility of preventing outbreaks among the most vulnerable populations living in high risk areas, where the usually recommended control measures are not sufficient. A global stockpile of oral cholera vaccine has been created, as an additional tool to help control cholera epidemics. Over the period July 2013 /June 2014 the stockpile will have available 2 million doses of vaccine.

Typhoid Fever

Typhoid fever is a bacterial disease caused by Salmonella enterica subsp. Enterica serovar Typhi (S. Typhi) consisting of an acute generalized infection of the reticuloendothelial system, intestinal lymphoid tissue, and gallbladder. The disease is transmitted through the intake of food or drink contaminated by feces or urine from infected people, and the condition, which may be mild or severe, occurs after a period of 1 to 3 wk. Usual symptoms include high fever, malaise, headache, constipation or diarrhea, rose-colored spots on the chest, and enlarged spleen and liver. A healthy carrier state may often follow acute illness.

The magnitude of the typhoid fever problem worldwide is difficult to quantify because the clinical picture is confused with that of many other febrile infections (including paratyphoid), and the capacity for routine bacteriological confirmation is absent in most areas of the less developed world. Typhoid fever is estimated to occur annually in more than 20 million people worldwide.¹⁵ With 1–4% mortality from invasive S. Typhi infection, the annual number of deaths is estimated to be 200 000–800 000 globally.¹⁶ Global estimates have assumed that most of the disease burden is in Asia, but only 3 vaccine trials and no population-based studies from Africa were available for inclusion in the estimates.¹⁷

Although the problems caused by S. Typhi have been recognized by the WHO and the GAVI Alliance (formerly Global Alliance for Vaccines and Immunization),¹⁸ the growing impact of S. enterica serovar Paratyphi A (S. Paratyphi A) is less widely appreciated.^19,20 Early estimates implicated S. Paratyphi A in approximately 5.5 million cases annually, predominantly in infants and children under 2 y of age.

Finally, it is very important to remind that the emergence of MDR (multiple-drug resistance) S. Typhi strains in the 1970s and 1980s led to widespread use of fluoroquinolones such as ciprofloxacin and ofloxacin in countries where MDR is a problem. In the early 1990s, outbreaks of typhoid fever caused by bacterial strains with decreased sensitivity to fluoroquinolones occurred in Tajikistan and Vietnam. S. Typhi strains showing complete resistance to ciprofloxacin were reported in 2005, first in Karachi (Pakistan) and more recently in India.²¹ Recent MDR outbreaks in several African countries (Ghana, Kenya, South Africa, Nigeria, Senegal) suggest widespread occurrence of such strains.

Typhoid vaccine is recommended for people traveling to developing countries. The risk of contracting the disease varies with type of travel, longer duration, eating behavior, and contact with local populations, and vaccine recommendations will therefore vary accordingly. Nevertheless, typhoid fever is well reported even in individuals on short, upscale itineraries.²² Typhoid vaccination should be recommended to all travelers going to very high risk countries. Short-term travelers to intermediate risk countries may consider vaccination if they are at high risk because of planned activities, or are risk averse and prefer maximum protection. Vaccine should also be recommended, regardless of travel duration, if the place of destination is an area where antibiotic-resistant strains of S. Typhi are prevalent.

Food and water precautions should be followed even if a traveler receives typhoid vaccination, as the vaccines are not fully protective and a large oral inoculum may overwhelm even an optimal antibody response.

Currently licensed, used, and commercially available typhoid vaccines include the following:

• Purified Vi polysaccharide parenteral vaccine

• Ty21a live attenuated oral vaccine

• Purified Vi polysaccharide conjugated to tetanus toxoid as a parenteral vaccine (one conjugate, so far, licensed in India)

Purified Vi polysaccharide parenteral vaccine

This consists of purified Vi capsular polysaccharide from the Ty2 S. Typhi strain. Purified Vi is available as a solution containing 25 μg of Vi polysaccharide in 0.5 mL of phenolic isotonic buffer. Each immunizing dose contains 25 μg of Vi polysaccharide, less than 1.25 mg of phenol in Typhim Vi® and 1.1 mg in Typherix®, and 0.5 mL (or as much as will suffice) of isotonic buffer (4.15 mg sodium chloride; 0.065 mg sodium dibasic phosphate, 2H₂O; 0.023 mg sodium monobasic phosphate, 2H₂O; and 0.5 mL [or as much as will suffice] of water for injection). The Vi vaccine, Typhevac inj®, manufactured by the Shanghai Institute of Biological Products contains 30 μg of Vi polysaccharide.

The vaccine induces a T-cell-independent IgG response that is not boosted by additional doses. The administration route of this vaccine is subcutaneous or intramuscular. The vaccine is licensed for individuals aged >2 y because the Vi vaccine does not elicit adequate immune responses in children aged <2 y. A single dose is required, and the vaccine confers protection 7 d after injection. To maintain protection, revaccination is recommended every 3 y. The Vi polysaccharide vaccine may be co-administered with other vaccines relevant for international travelers—such as yellow fever and hepatitis A—and with vaccines of the routine childhood immunization programs.

The Vi polysaccharide vaccine elicits serum IgG Vi antibody responses in 85–95% of adults and children aged >2 y and provides approximately 70% protection for up to 3 y in older children and adults.²³ A serum Vi antibody level of at least 1.0 μg per mL has been proposed as a serological correlate of protection against typhoid fever.

This subunit vaccine was first licensed in the United States in 1994, and is available in more than 93 countries worldwide. There are currently 2 licensed manufacturers of purified Vi in industrialized countries, Sanofi Pasteur Vaccines (Typhim Vi®, available in the United States and many European and other countries) and GSK Biologics (Typherix®, available in many European and other countries). In addition, several vaccine manufacturers in Asia (India, China, South Korea, Vietnam), Russia, and Cuba²⁴ make Vi products for local and regional consumption.

Purified Vi polysaccharide behaves like a T-lymphocyte-independent antigen. Like other T-cell-independent purified polysaccharide vaccines, Vi is not a good immunogen in infants.

Most infants do not respond, and among those who do, responses are meager and short-lived. More importantly, serum antibody response is not boosted by administration of additional doses of Vi vaccine in older children or adults and (as with other purified polysaccharide vaccines) there is no evidence of immune memory. Administration of subsequent doses may induce a lower serological response as compared with primary vaccination. Hyporesponsiveness has not been specifically looked for with the Vi vaccine. However, some data suggest that the response to a re-immunization with Vi 2 to 3 y after the initial immunization, when antibody titers have fallen, does not fully restore the titers to the peak level seen after initial immunization.^25,26

There are no contraindications to immunization with the Vi polysaccharide parenteral vaccine other than known hypersensitivity to any component of the vaccine. Although the Vi polysaccharidevaccine is safe for HIV-infected individuals, induction of protective antibodies is directly correlated with levels of CD4-positive T-cells. It is very well tolerated, with fever or flu-like symptoms reported in less than 1% of recipients. The Vi vaccine has also proved to be well tolerated and safe when co-administered with routine childhood vaccines.

Ty21a live attenuated vaccine

This vaccine is an orally administered, live attenuated Ty2 strain of S. Typhi in which multiple genes, including those responsible for production of Vi, have been mutated chemically. Ty21a is currently formulated as enteric-coated capsules (2 to 6 × 10⁹ CFU/capsule) for oral administration on alternate days of 3 doses in endemic settings and 3–4 doses as a travel vaccine (4 in Canada and USA). It is recommended for individuals at least 5 y of age. There are very limited data to guide situations of interrupted Ty21a vaccine courses; a general guideline is that if less than 3 wk have elapsed since the last dose, one may continue to complete immunization with the missing doses. If more than 3 wk have elapsed, the full regimen of this well-tolerated vaccine should be administered de novo.

With the 3-dose regimen, protective immunity is achieved 7 d after the last dose. In Australia and Europe, the recommendation is to repeat this series every 3 y for people living in endemic areas and every year for individuals traveling from non-endemic to endemic countries. In North America, a booster dose is recommended after 5 y (USA) or 7 y (Canada) for all, regardless of typhoid fever endemicity in the country of residence.

Capsules should be taken on an empty stomach with cold or lukewarm (no more than 37 °C) water or milk and should be kept refrigerated between doses. Although the vaccine should be kept refrigerated at 2–8 °C, it maintains its stability when kept at 25 °C for up to 7 d, and exposure to a higher room temperature of 37 °C for less than 24 h does not affect its potency.²⁷

Oral Ty21a should not be administered in the presence of nausea, vomiting, or diarrhea and should be used with caution in people with inflammatory bowel disease or other ulcerative conditions of the gastrointestinal tract.

Ty21a vaccination results in robust cell-mediated immune responses (stimulates both CD4+ helper T-cell and CD8+ cytotoxic T-cell responses, both of which are believed to play roles in defense against S. Typhy), immune memory and prolonged protection of 60–70% over 7 y in individuals with ongoing exposure to environmental salmonella in endemic areas.^28,29 Adequate efficacy studies in travelers have not been conducted.

Field data also suggest that Ty21a results in herd protection³⁰ and confers cross protection against S. Paratyphi B but not S. Paratyphi A.^31-33

Ty21a is remarkably well tolerated and has low adverse event rates. The most common side effect associated with the Ty21a is abdominal discomfort; other side effects include nausea, vomiting, rash, urticaria, or headache.

As a general rule, Ty21a should not be given to pregnant women, although no adverse effects have been reported in the pregnant woman or fetus (pregnancy class C). Caution should similarly be taken before anyone with a known depression of cell-mediated immunity is given Ty21a, but it is recommended for human immunodeficiency virus – positive individuals with CD4 + count >200.

Use of antimicrobials should be discontinued 2 to 3 d before administration of the first dose. The same time interval between administration of the Ty21a vaccine and the antimalarial drugs proguanil, mefloquine, and chloroquine has traditionally been recommended, but various studies have modified these recommendations.³⁴ It is now acceptable to administer this vaccine while receiving antimalarial drugs, including mefloquine, atovaquone/proguanil, chloroquine, and primaquine.³⁵

This vaccine was first licensed in Europe in 1983 and in the USA in 1989. Since it was first licensed, Ty21a has been used predominantly by travelers to S. Typhy endemic countries although it is licensed in 56 countries worldwide. Ty21a is now manufactured by 3 companies: Janssen of Switzerland (Vivotif®), Boryung Pharmaceutical Co., Ltd., of South Korea (Zerotyph®), and Sanofi Adventis Pharma India (Typhoral®).Under license, Ty21a is also distributed by a number of other vaccine distributors.

In 1997, the liquid formulation of Ty21a was licensed by a number of countries with a 3-dose immunization regimen that recommends a 2-d interval between doses. However, this formulation did not gain popularity among travelers and its manufacture was therefore discontinued.

Purified Vi polysaccharide conjugated to tetanus toxoid as a parenteral vaccine

One Vi polysaccharide conjugate vaccine consisting of Vi covalently linked to tetanus toxoid, Peda Typh®, has been licensed in India based on a relatively small multisite clinical trial that demonstrated safety and immunogenicity (serum anti-Vi antibodies) of the vaccine in infants and children.³⁶ One vial of Peda Typh® contains a single dose (0.5 mL) of conjugate consisting of 5 μg of S. Typhy Vi polysaccharide conjugated to 5 μg of tetanus toxoid protein in isotonic saline.

In subjects older than 2 y, Peda Typh® Vi conjugate vaccine is administered intramuscularly in a 2-dose schedule with 4 to 8 wk between the doses. A booster is recommended every 10 y. No data are available with this particular Vi conjugate to support the timing of booster doses. For children aged 3 to 23 mo, 2 doses of vaccine are recommended 4 to 8 wk apart. The manufacturer also recommends a booster every 10 mo for those initially immunized at this young age.

The only Vi conjugate vaccine licensed (in India), Peda Typh, was approved based on clinical data supporting its safety, clinical tolerability, and immunogenicity. However, it was not evaluated for efficacy in randomized controlled field trials, and no estimates of efficacy are therefore available.^37,38

Hepatitis A

Approximately 1.4 million cases of hepatitis A are recorded every year worldwide. The hepatitis A virus is transmitted through the intake of contaminated food or drink, or by direct contact with a person infected by the virus. There are geographic areas with high, intermediate, and low risk of HAV infection.

Improved sanitation and the hepatitis A vaccine are the most effective measures to fight the disease.

There are 2 types of monovalent hepatitis A vaccines marketed worldwide: formaldehyde-inactivated vaccines, widely used in most countries, and live attenuated vaccines, used in China and in the private medicine sector in India.³⁹

Inactivated vaccines contain antigens derived from attenuated HAV strains (95% homology between strains) obtained from cell cultures. Differences lie in the viral purification process.

Table 1 shows the different adjuvants and antigen doses. The dosage and age of use of the different presentations are shown in Table 2. AVAXIM® is the only commercial presentation including phenoxyethanol as preservative. No vaccine contains antibiotics, but antibiotic traces derived from the production process may be found in HAVRIX® (neomycin), AVAXIM® (neomycin), and EPAXAL® (polymyxin B).³⁹

Table 1. Inactivated hepatitis A vaccines^39,40

Trade name	Attenuated HAV strain	Adjuvant	HAV antigen Dose/injection Paediatric/adult	Manufacturers
HAVRIX	HM-5	Alum hydroxide	720EU /1440 EU	GSK Biologicals
VAQTA	CR-326	Aluminum hydroxyphosphate sulfate	25U /50 U	Merk Sharp and Dohme Corp.
AVAXIM	GBM	Alum hydroxide	80U / 160 U	Sanofi Pasteur
EPAXAL	RG-SB	Virosomes (10 µg purified influenza virus haemagglutinin and 100 µg of phospholipids)	12 U / 24 U	Crucell
HEALIVE*	TZ84	Alum hydroxide	250 U / 500 U	Sinovac Biotech Ltd
Weisairuian*	Lv-8	Alum hydroxide	320EU / 340EU	Institute of Medical Biology of the Chinese Academy of Medical Sciences

* Only available in China.

Table 2. Dosage and age of use of the different adult and pediatric presentations (available worldwide)

Name of vaccine	Antigen units HAV	Dosing schedule	Comments
Avaxim^™	160	0.5 mL IM 0, 6–12 mo	≥12 y old;
Avaxim Pediatric^™	80	0.5 mL IM 0, 6–36 mo	1–15 y old
HAVRIX^® 1440	1440 ELISA	1.0 mL IM 0, 6–12 mo	19 y and older
HAVRIX^® 720	720 ELISA	0.5 mL 0, 6–12 mo	1 to 18 y
VAQTA^®	50	1.0 mL 0, 6 mo	18 y and older
VAQTA^® Pediatric	25	0.5 mL 0, 6–18 mo	1 to 17 y
EPAXAL^®	24	0.5 mL 0, 6–12 mo	>1 y
EPAXAL^®Junior	12	0.25 mL 0, 6–12 mo	1 to 16 y

Data taken from refs. 52 and 53.

Live attenuated virus vaccines are only marketed in China (Weisairuiji®, NA®, HAVAC®) and are administered by the subcutaneous route to children older than 1 y. Attenuation is achieved through sequential cell culture passages. Use of these vaccines is limited to routine immunization of children.⁴¹

Both inactivated and attenuated vaccines are highly immunogenic. Both types of vaccine induce similar responses and generate long-lasting protection against hepatitis A in children and adults. The different studies conducted with inactivated vaccines report a very good humoral response, with very high seroprotection levels at 14 d and achievement of 100% protection 4–6 wk after the first dose.³⁹ A single dose of hepatitis A vaccine induces immune memory, with appearance of anti-HAV persisting over observation periods of 4 and 11 y.⁴¹ Immunization with 2 doses, regardless of the time interval between both, produces protective immunity lasting decades, and possibly lifetime protection.^39,42,43 Various clinical studies conducted with live attenuated vaccines showed a response similar to that of inactivated vaccines, with 98% seroconversion 28 d after vaccination and protective immunity 15 y after primary immunization.^44,45

Inactivated HAV vaccines may be administered simultaneously with other inactivated and attenuated vaccines without interfering with the immunogenicity, reactogenicity, or safety of each of them. All inactivated HAV vaccines are exchangeable, without altering the immune response.^40,41

All non-immune travelers over 1 yr of age traveling to areas with intermediate or high risk of hepatitis A should be vaccinated. In travelers with underlying conditions such as chronic liver disease or immunosuppressed, hepatitis A vaccination should be promoted (because of their increased risk of severe complications in the event of hepatitis A virus infection).⁴⁶

The British Society for Rheumatology recommends hepatitis A vaccination for travelers who require immunomodulatory treatment involving intermediate or low immunosuppression, restricting use of immunoglobulins to cases of severe immunosuppression.⁴⁷ In HIV patients, response to the vaccine will depend on CD4 levels.⁴⁸

The safety of hepatitis A vaccines in pregnant female travelers has not been established. With inactivated hepatitis A vaccines, the theoretical risk for both the mother and fetus would be very low. During pregnancy, the benefit and risk of these vaccines should be weighed when traveling to an area where a high exposure to the hepatitis A virus exists.⁴⁹

In the event of international adoption, vaccination against HAV is recommended to all people living with the adopted child, because outbreaks related to adoptions have been recorded in host countries in recent years.⁵⁰

It should be noted that, due to rapid seroconversion after administration, hepatitis A vaccination is justified in last minute travelers.⁵¹

Inactivated vaccines are approved for administration by the intramuscular route as a 2-dose schedule from 12 mo of age. The dose interval is flexible (from 6 mo to 4–5 y), but usually ranges from 6 and 18 mo.

Healive® is the inactivated vaccine marketed in China as both a presentation for adults (1mL, 500 U HAV antigen) for people older than 15 y and a pediatric presentation (0.5 mL, 250 U HAV) for children aged 1–15 y.

Inactivated hepatitis A vaccines have an excellent safety profile, regardless of the vaccination scheme and the manufacturer. Fifty percent of vaccinated adults experience local reactions such as pain or inflammation at the injection site, but these are less common in children. Headache and malaise have also been reported in 14–16%. No serious adverse effects associated to inactivated hepatitis A vaccines have been reported.^41,49

Inactivated hepatitis A vaccines are used in most countries worldwide, while distribution of the attenuated vaccine manufactured in China is restricted to Asian countries.³⁹

Combined hepatitis A/B vaccines

Hepatitis A/B vaccines (Twinrix Paediatric® and Twinrix Adult®) are indicated for use in non-immune travelers >1 y of age (≥16 or ≥19, depending on country licensing) who are at risk of both hepatitis A and hepatitis B infection.

The adult combination vaccine (Twinrix Adult®) contains 720 ELISA units of hepatitis A antigen and 20 µg of recombinant hepatitis B surface antigen (HBsAg) in each 1 mL dose. The pediatric combination vaccine (Twinrix Paediatric®) contains 360 ELISA units of hepatitis A antigen and 10 µg of HBsAg in each 0.5 mL dose. Three doses are administered at 0, 1, and 6 mo.⁵⁴

Ambirix® (GSK), another hepatitis A/B vaccine, is indicated for use in non-immune children aged 1 to 15 y. Ambirix® is exactly the same product as Twinrix Adult®, and therefore contains twice as much inactivated HAV as Twinrix Paediatric®. It is administered as 2 doses given 6–12 mo apart.^55,56

All combined hepatitis A/B vaccines contain trace amounts of neomycin, alum hydroxide, and aluminum phosphate as adjuvants.

The advantage of the Twinrix Paediatric® 3-dose regimen is that a higher degree of protection (especially against hepatitis B) can be expected between months 1 and 6 as compared with a 2-dose Ambirix® regimen. Therefore, the choice between these 2 products depends on how quickly it is desired to elicit a high level of immunity to both viruses. If there is no hurry, the 2-dose Ambirix® scheme may be preferred due to the lesser number of injections.⁵⁵

For Twinrix Adult®, when travel is anticipated within 1 mo or more after starting the vaccination course, a schedule of 3 intramuscular injections given at 0, 7, and 21 d may be used. When this schedule is used, a fourth dose is recommended 12 mo after the first.⁵⁶

Combined hepatitis A and typhoid fever vaccines

Combination vaccines (Hepatyrix®, Vivaxim®, ViATIM®) containing Vi polysaccharide typhoid vaccine and inactivated hepatitis A vaccine are available in many countries for vaccination against both diseases.⁴⁰

ViVaxim™ or ViATIM, manufactured by Sanofi Pasteur Ltd, combines purified Vi polysaccharide typhoid vaccine in solution (25 µg of the Vi polysaccharide typhoid vaccine) and inactivated hepatitis A vaccine in suspension (160 antigen units) in a single-dose, for intramuscular administration to individuals over 16 y of age.⁵⁷

Hepatyrix® combines 25 µg of Vi polysaccharide of S. Typhi (Ty2 strain) and 1440 ELISA units of hepatitis A antigen (HM175 strain) and should be administered as a single intramuscular dose to subjects older than 15 y of age.

With all these products, a second dose of hepatitis A vaccine is needed at 6 mo to complete vaccination against hepatitis A.

Hepatitis E

Approximately 20 million cases of hepatitis E virus infection occur every year. Of these, more than 3 million are severe acute cases of hepatitis E, resulting in 57 000 deaths. Hepatitis E affects all parts of the world, but has a greater prevalence in East and South Asia. Different genotypes of the hepatitis E virus determine differences in epidemiology; for example, genotype 1 is usually seen in developing countries and causes community-level outbreaks, while genotype 3 is usually seen in developed countries and causes no outbreaks. There are 2 presentation patterns of disease: a non-endemic pattern of sporadic cases in developed countries, and an endemic pattern in developing countries which is associated to large epidemics and high mortality in pregnant women (10–25%).^58,59

Pregnant women are at greater risk of obstetrical complications and mortality from hepatitis E, which may induce a 20% mortality rate in pregnant women in their third trimester. Chronic hepatitis E and reactivations of the infection have been reported in immunosuppressed people.

The disease is transmitted through feces and water, and contaminated water or food supplies have been implicated in major outbreaks. Ingestion of raw or uncooked shellfish has also been identified as a source of sporadic cases in endemic areas.

The first vaccine against the hepatitis E virus (Hecolin®, Innovax) was marketed in China in October 2012 after approval by China`s State Food and Drugs on December 2011. Hecolin® is a recombinant Escherichia coli vaccine.⁶⁰

Immunogenicity of the vaccine is due to E. coli-expressed HEV239 protein, part of the pORF2 protein of hepatitis E virus genotype 1, a component of the viral capsid, where most epitopes triggering immune response are located.⁶¹

Because of the short time elapsed from marketing of the vaccine and the geographic limitation of its use in China, vaccination of international travelers is not indicated for the time being. The WHO has made a call to convene an expert panel and prepare a position document on vaccination against hepatitis E planned for the beginning of 2015.⁶² In China, use of the vaccine has been approved in high risk patient groups older than 16 y and younger than 65 y. These groups include women of childbearing age, food handlers, elderly people, transplant receptors, and travelers to endemic areas. The manufacturing company expects that this indication is extended in the near future to pregnant women, patients with chronic liver diseases, and children younger than 2 y.⁶¹

The vaccine schedule consists of intramuscular administration of 3 doses of 30 µg of HEV 239 adsorbed into alum hydroxide and suspended into 0.5 mL of saline buffer, with dose intervals of 0, 1, and 6 mo. Vaccine efficacy is 100% at 13 mo, and a high efficacy is achieved from the second dose. This justifies its potential future indication in both international travelers and outbreaks.⁶³ Results of the different clinical trials have shown no unexpected general adverse effects, and only 2.8% of local reactions. The vaccine is usually well tolerated even in pregnant women.⁴² Further studies are needed to assess long-term immunity, protection against different genotypes, and potential use in international travelers, military personnel, and voluntary workers.

Rotavirus

Rotavirus is the most common cause of severe diarrheal disease in young children throughout the world. The risk for adult travelers is negligible because most individuals will have good immunity as the result of repeated exposure in early life. However, children under the age of 5 y are at risk. Vaccines for rotavirus may currently not be routinely recommended in infant immunization schedules or available in some countries. Children who travel should receive these vaccines if they are not part of vaccination schedules.

Rotavirus has been found in approximately 10% of patients with traveler’s diarrhea⁶⁴ and is highly endemic in developing countries. While food appears to be the primary mode of transmission for E. coli, Shigella and Salmonella and norovirus, water seems to be the primary vehicle through which rotavirus is transmitted.⁶⁵

The classic presentation at all age groups consists of fever and vomiting for 2–3 d followed by non-bloody diarrhea (10–20 bowel movements daily), which may rapidly lead to severe dehydration, especially in infants. In healthy adults, viral enteritis tends to be milder and usually lasts for a few days only, leaving protective immunity against infecting serotypes. However, in immunocompromised patients, rotavirus may cause chronic and recurrent diarrhea.⁶⁶

Most episodes occur in young children, particularly between the ages of 3 mo and 2 y. Symptoms usually appear approximately 2–3 d after infection (projectile vomiting and very watery diarrhea, often with fever and abdominal pain). The virus spreads rapidly, presumably through person-to-person contact, airborne droplets or, possibly, contact with contaminated toys. Viruses replicate in the enterocytes of the small intestine, causing extensive damage to microvilli and resulting in malabsorption and loss of fluids and electrolytes. These viruses cause a great mortality (approximately 500 000 deaths annually), mainly among children under 5 y of age from countries of Africa and Asia, as well as a high morbidity in more developed countries. In most low income countries in Asia and Africa, rotavirus epidemiology is characterized by one or more periods of relatively intense rotavirus circulation against a background of year-round transmission, whereas in high income countries with temperate climates a distinct winter seasonality is typically observed. This difference, as well as differences in health care availability and childhood co-morbidity, drives the marked inequality in rotavirus disease burden between low and high income countries.^67,68

In low income countries, median age at the primary rotavirus infection ranges from 6 to 9 mo (80% occur among infants <1 y old), while in high income countries the first episode may occasionally be delayed until the age of 2–5 y, though the majority still occur in infancy (65% occur in infants <1 y old).

Rotaviruses contain a genome encoding for 6 structural viral proteins (VPs) and for 5 to 6 non-structural proteins (NSPs). The outermost viral envelope contains proteins VP7 and VP4, which induce production of neutralizing antibodies in the host and are therefore considered important for protective immunity. In human rotaviruses, at least 12 different VP7 antigens (G-types) and 15 different VP4 antigens (P-types) have been identified. As the combination of G- and P-types can vary independently, a binomial typing system is used to identify strains. Currently, 5 G-P combinations (G1P[8], G2P[4], G3P[8], G4P[8]) and G9P[8]) account for approximately 90% of all human rotavirus infections in many parts of the world; the most prevalent combination is the type G1P[8]. However, data from countries in Asia and Africa show greater strain diversity, with several rotavirus types circulating simultaneously. The prevalent types may vary from one season to the next, even within the same geographical area. The type of rotavirus does not usually correlate with disease severity.⁶⁷

Two new rotavirus vaccines to prevent severe rotavirus disease are now available. They both are oral live attenuated rotavirus vaccines with strains of human and/or animal origin that replicate in human bowel, Rotarix® (a monovalent vaccine (RV1) from GlaxoSmithKline Biologicals) and RotaTeq® (a pentavalent vaccine (RV5) from Merck and Co. Inc.), are available internationally. Both vaccines are considered safe and effective for preventing gastrointestinal disease. Other vaccines against rotavirus are marketed in China (Lanzhou lamb rotavirus vaccine, manufactured by the Lanzhou Institute of Biomedical Products) and Vietnam (Rotavin-M1, manufactured by Polyvac) but these are not internationally available.

Rotarix® is a monovalent live virus vaccine, 1 mL of which contains no less than 10⁶ CCID50 of human rotavirus (G1,P[8] strain isolated from a case of infantile gastroenteritis) attenuated in Vero cells. The vaccine should be kept at 2–8 °C protected from light, and should not be frozen. The vaccine shelf-life is 3 y. The volume is 1 mL for the lyophilized formulation and 1.5 mL for the liquid formulation. It is administered by the oral route as 2 doses at least 4 wk apart. It is recommended that the first dose is administered at 6 wk of age, and the second dose at 24 wk.

RotaTeq® is a pentavalent live virus vaccine (G1,G2,G3,G4, P1) of human-bovine rotavirus attenuated in Vero cells. Four WC3-based reassortants express one of the VP7 proteins G1, G2, G3, or G4 from the human strains and the VP4 protein P7[5] from the bovine strain, whereas the fifth reassortant virus expresses the VP4 protein P1A[8] from a human strain and the G6 protein from the bovine parent strain. The 5 reassortant strains are suspended in a solution of buffer (2 mL) and stabilizer that should be stored at 2–8 °C and should not be frozen. The vaccine is usually administered by the oral route as 3 doses at 2, 4, and 6 mo of age, but any schedule in which the first dose should be administered between 6–12 wk of age and subsequent doses at 4–10-wk intervals is considered adequate. The minimal age for the first dose is 6 wk, and vaccine should not be administered after week 32 of life.

These rotavirus vaccines for infants should be included in all national immunization schedules.⁶⁷ The WHO recommends that the first dose of either RotaTeq® or Rotarix® is administered at 6–15 wk of age. The interchangeability of RV1 and RV5 has not been tested. These vaccines may be administered simultaneously with other vaccines in the infant immunization schedule.

Recent data show that, at the end of 2012, vaccination against rotavirus was administered in 41 countries and worldwide coverage was estimated at 11%.⁶⁹ Introduction of Rotarix® or Rotateq® in vaccination schedules has been shown to markedly decrease the number of cases of diarrhea, severe diarrhea, hospitalization, and medical visits for diarrhea in the 2 y following vaccination.

The review conducted by Soares-Weiser et al. of 34 trials with approximately 175 944 participants concluded that Rotarix® and RotaTeq® are effective vaccines, and support the WHO recommendation to include rotavirus vaccination of infants into national immunization programs, especially in countries with a high burden of diarrheal deaths in children under 5 y of age. Further head-to-head comparison trials with both vaccines are needed, as well as trials comparing LLR with placebo, data for special groups of children, such as preterm infants and malnourished children, and extensive monitoring of adverse events where vaccines are routinely used.⁷⁰

However, in some, but not all settings, post-marketing surveillance has detected a small increase in the risk of intussusception (approximately 1–2/100 000 infants vaccinated) shortly after the first dose. Still, the benefits provided by rotavirus vaccination through prevention of severe diarrhea and death from rotavirus infection far exceed the risk of intussusception.

In large controlled trials, no differences were seen between the vaccine and placebo groups in terms of serious adverse events. Serious allergic reactions (e.g., anaphylaxis) after a previous dose and severe immunodeficiency, including severe combined immunodeficiency, are contraindications for rotavirus vaccination. Caution should be taken if there is a history of intussusception or intestinal malformations, chronic gastrointestinal disease, and severe acute illness. Vaccination should be postponed in case of ongoing acute gastroenteritis or fever with moderate to severe illness.⁶⁷

Breastfeeding and prematurity (<37 wk gestation) do not appear to significantly impair response to rotavirus vaccines. Contraindications for use of rotavirus vaccines include severe hypersensitivity to any of their components and severe immunodeficiency, including severe combined immunodeficiency (SCID). Vaccination should be postponed in case of ongoing acute gastroenteritis or fever with moderate to severe illness. These vaccines are not routinely recommended for infants with history of intussusception or intestinal malformation possibly predisposing for intussusception.⁶⁷ Because most severe cases of rotavirus gastroenteritis occur earlier in life, vaccination of children older than 24 mo is not encouraged.

There is a good balance between benefit and harm for Rotarix® and RotaTeq® vaccines, but future trials should plan head-to-head comparison of both vaccines. These comparative data may be helpful for decision makers. Both vaccines show 80–90% efficacy against severe diarrhea in countries with very low or low child and adult mortality, and 40–60% efficacy in countries with high child mortality and high or very high adult mortality.

Cost-effectiveness studies of rotavirus vaccines vary depending on the country, with different incidence rates, prices, and vaccine coverage. Estimates of the annual cost per disability-adjusted life year averted and of the proportion (%) of rotavirus deaths averted through introduction of rotavirus vaccines vary between US $8 and US $87, and 32% and 44%, for Afghanistan and Bangladesh respectively. For India, the country with the highest number of recorded deaths due to rotavirus, the corresponding values were US $57 and 34%, whereas for the Democratic Republic of Congo, Ethiopia, and Nigeria these figures ranged from US$ 19–27 and 28–31%.⁶⁷

It should finally be noted that improved educational, health and global development in economically most disadvantaged countries will lead to a decreased risk of transmissible diseases which will result in a decreased incidence and mortality of infectious diseases. As regards traveler diseases preventable by vaccination, many clinical trials are currently ongoing to assess new vaccines against both the diarrheal and gastroenteric diseases analyzed (improving their immunogenicity, safety, and costs) and other diseases not mentioned here which may be prevented with vaccines. The WHO has defined the 2010–2020 period as the vaccine decade, during which it is intended to improve use of current vaccines (including vaccines against cholera, typhoid fever, and rotavirus) by promoting their widespread use in risk areas, evaluate new indications in travelers such as hepatitis E, or introduce new vaccines for conditions for which vaccination has not been available yet.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

10.4161/hv.27737