The Pharmaceutical Journal Vol 265 No 7124 p792-797
November 25, 2000 Continuing education

Travel medicine

(7) Travel vaccinations

By Larry Goodyer, PhD, MRPharmS

Travel medicine article index

For the majority of travellers, vaccinations are seen as the most important preparation for a healthy trip abroad. In truth, the risk of contracting many immunisable diseases is quite small. An overemphasis is sometimes placed on vaccinations to the detriment of other diseases which may present a greater risk. Despite this observation, it would not be appropriate to discourage people from obtaining vaccinations, if appropriate for their destination. Vaccination has another important function — it brings the traveller into contact with the health system, providing an opportunity to educate travellers on wider travel health issues.
This article examines the general principles associated with travel vaccinations and give a more detailed consideration of the vaccines in current clinical use. Childhood vaccinations are not discussed, although it is important to note that, where possible, they should be completed before travel to certain destinations.

Role of the pharmacist and place in the NHS

Pharmacists play an important role in giving advice on travel vaccinations. Travellers often make initial inquiries about vaccinations to a pharmacist before visiting their general practitioner. Therefore, pharmacists should be in a position to outline travel requirements using the databases described in the first article in this series.¹
In recent years, general practitioners (GPs) have tended to acquire practice stocks of vaccines (rather than obtaining them by prescription) and much of the role of running vaccination clinics has been assigned to a practice nurse. However, an increasingly important role for pharmacists is in practice support, for example, by devising practice protocols or by arranging efficient supply and correct storage of vaccines. Storage procedures apply to all vaccines and the importance of maintaining a cold chain is discussed elsewhere.^2,3
There is an ongoing debate about whether it is appropriate for the National Health Service to provide travel vaccines. It can be argued that by supplying such vaccines, the Government is, in effect, subsidising an individual's holiday. The only real counter-argument to this, in economic terms, is to consider the potential cost of treating disease contracted abroad or spread by travellers on return. If the risks of contracting the disease, and mortality from it, are low then it may be difficult to justify NHS supply. For example, hepatitis A carries a moderate risk in some parts of the world but has a generally low mortality. A pharmacoeconomic analysis of widespread vaccination against hepatitis A has suggested an argument against regular vaccination to some low-risk destinations.⁴ Vaccinations against diseases which are perceived to be a danger to the United Kingdom population are generally provided to travellers on the NHS. However, vaccination for a disease such as yellow fever, which is carried by a species of mosquito not native to the UK, must be obtained privately. In such cases, GPs may charge patients for the cost of the vaccine and an additional administration charge. In some cases, the vaccine can be prescribed on the NHS but an administration charge may be made at the discretion of the practice. This has led to variations in charges between practices, and it may be advisable for travellers to compare charges at different GPs and private vaccination clinics. If travellers receive vaccinations from more than one clinic, it is important that vaccination record books are kept up to date.
The characteristics of travel vaccines, including their availability on the NHS, are shown in Table 1.

Immunology and types of vaccine used in travel medicine

The principle behind vaccination is that the immune system is stimulated by the introduction of material that it recognises as foreign, ie, antigenic. If the antigens are the same as, or similar to, those present in the organism responsible for the disease, then cellular and/or antibody immune mechanisms will be directed against the organism. After a primary response to the vaccine, the immune system "remembers" the antigen and subsequent contact will elicit a more intense immune stimulation. Therefore, the individual will be immune if the pathogenic organism is actually encountered.
Vaccines can be broadly divided into those that contain a live but harmless (attenuated) form of the virus, those which contain a whole killed organism and others comprising a component of the organism that will stimulate the immune system. Live vaccines tend to require only a single dose to ellicit the necessary immune response against the disease, although those given orally, such as polio or typhoid, require multiple doses. Other types of vaccines tend to require a primary course of injections, but there are exceptions such as typhoid and meningitis A and C. After a period of time, immunity declines and a single-dose booster of the vaccine is required. Of particular relevance to travel medicine is that after the primary vaccination course, the antibody response can take two to four weeks to develop, whereas a booster will be effective after just a few days.
The process of immune stimulation is referred to as active immunisation. It is also possible to use passive immunisation where antibodies (immunoglobulins) are injected which confer immediate protection. Immunoglobulins are usually used for post-exposure treatment; the only occasional exception is for the prevention of hepatitis A.
In diseases such as diphtheria and typhoid, the pathological changes are caused by a toxin released by the organisms. Therefore, vaccines against the toxin rather than against the organism are used.
Various methods are employed to produce vaccines. Organisms may be cultured and then inactivated or killed. In other cases, modern techniques using recombinant DNA are used. An antibiotic is sometimes added to vaccines to act as a preservative and potential problems with antibiotic sensitivity should be recognised.

Regimen planning

It is desirable for travellers to plan vaccinations about eight weeks before travel but, because this is not always possible, vaccines may need to be given quite close to departure. In such cases, the traveller should be made aware that the vaccine has given them reduced immunity, so other measures, eg, hygiene, should be emphasised. The precise regimens for each vaccine are described in Table 2 and are discussed in some detail below.
In general, inactivated vaccines will not interfere with each other or with live vaccines, so they can be administered at one appointment. Live vaccines can be given together but at different sites, or on separate occasions three weeks apart. This is because of the theoretical possibility of impaired immune response to both vaccines; however it does not apply to the childhood vaccines MMR and oral polio. There are some theoretical concerns about giving immunoglobulins against hepatitis A with live vaccines, because the immunoglobulins could potentially kill live viruses. However, normal immunoglobulin would not contain antibodies against yellow fever and can also be used at the same time as oral polio vaccine.

Adverse reactions

Reactions are frequently mild, consisting of low-grade fevers, muscle pains and fatigue. These symptoms will usually resolve within a day or so and are effectively relieved by paracetamol. Local reactions of pain and swelling around the site of injection are also quite common and can take more than 48 hours to resolve. In most cases, pharmacists can provide reassurance to those suffering minor adverse effects of vaccination. A more severe reaction may be observed rarely, and any skin reactions distant from the site of injection should be referred. More serious systemic allergic responses, eg, angioedema or anaphylaxis usually occur very soon after vaccination and need urgent medical attention. Allergy may be expected in some cases, for example, yellow fever vaccine is grown in chick embryos and may produce a reaction in people allergic to egg products. Similarly, those who are allergic to antibiotics may be at risk from the traces present in some vaccines. Certain individuals react to thiomersal, which is used as a preservative in a few vaccines.
A problem associated with multiple vaccination is that it may be difficult to identify the cause of an adverse reaction.
There are a few drug interactions or contraindications associated with vaccination. Chloroquine reduces the response to rabies vaccine if this is administered via the intradermal route,⁵ probably because of an immune impairment caused by chloroquine. This may also apply to mefloquine, but there is little evidence that such an interaction occurs.⁶ Mefloquine and other antibiotics should not be administered at the same time as oral typhoid. Intramuscular injections should be avoided by patients on anticoagulant therapy.

Groups for special consideration

Particular consideration needs to be given to children and this is discussed later in this article under each vaccine, although routine childhood vaccinations will not be covered. As a general rule, live vaccines should be avoided in pregnancy and breast feeding. However, if travel to high-risk areas cannot be avoided, yellow fever and oral polio may be given. Live vaccines should also be avoided in people who are immunosuppressed, for example, people with HIV or leukaemia and people receiving immunosuppressive chemotherapy or high-dose corticosteroids. People should not be vaccinated while they have moderate or severe fevers because of the possibility of a reduced immune response, and because it may be difficult to distinguish vaccine side effects from symptoms of fever.

Individual travel vaccines

Use and administration of vaccines is summarised in Tables 1 and 2. This section looks at individual vaccines and concentrates on the types of travellers who should be vaccinated, areas of risk for the diseases, effectiveness of the vaccines and special considerations.

Hepatitis A Among the diseases preventable by vaccination, hepatitis A is one of the most common. For instance, it is 100 times more likely to be contracted by travellers than typhoid. It is possible to test for antibody status in order to avoid vaccination, but this is rarely performed and vaccine can be given safely to those who have previously contracted the disease.
Until a few years ago, immunoglobulins were widely used for prophylaxis against hepatitis A. Apart from being a blood-derived product which is often in short supply, the resulting passive immunisation affords, at best, 90 per cent protection against hepatitis A.⁷ The more immunoglobulin that is administered, the longer the protection but, as only 5ml can conveniently be given prior to travel, no more than six months' protection can be expected. Even for short trips by occasional travellers, hepatitis A vaccine is usually the preferred, but somewhat more expensive, choice. The vaccine may be given together with hepatitis B, where a synergistic action has been claimed.⁸
A potential drawback of vaccination is that effective immunity may not be reached until about two weeks after the injection. The concurrent administration of immunoglobulins in those at high risk and in those vaccinated less than two weeks before departure has been advocated. However, as hepatitis A can take a few weeks to develop, some experts feel that such a regimen is unnecessary and can suppress the response to the vaccine.
It has also been debated whether the vaccine is needed in young children, who are likely to have a subclinical or very mild infection. The counter argument to this is that a few children can suffer a more serious course of infection and that they may transmit the disease to older children and adults.⁹ Once contracted, lifelong immunity is developed and immunisation is not necessary. Improved hygiene in developed countries has resulted in a reduced incidence of hepatitis A, hence there is an increased risk to travellers.
Hepatitis A vaccine is indicated for travellers visiting many developing countries including Africa, the Middle East, South America and Asia.

Hepatitis B It is not common practice in the UK to vaccinate low-risk travellers against hepatitis B, but in some developed countries it forms part of the routine vaccination programme. Hepatitis B is a disease transmitted through blood products, poorly sterilised surgical equipment and sexual contact. The risk of contracting hepatitis B is at its highest in sub-Saharan Africa and in parts of South East Asia and South America. In the UK, 12 per cent of all cases of hepatitis B have been attributed to travel.8 Vaccination should be recommended to long-term travellers, people who routinely visit endemic areas, high-risk groups such as those likely to engage in unprotected sexual activities, health workers, and anyone who might need medical or dental procedures. The consequences of hepatitis B are more chronic than hepatitis A, with an increased risk of liver failure and cancer.
Hepatitis C is similar to hepatitis B. It can be caught in the same way and is as big a problem worldwide, but there is no vaccine available.
From the schedules described in Table 2, it can be seen that advance planning of vaccinations six months before travel is normally required. This can be reduced to one or two months for travellers using the rapid schedules and some protection may be afforded after the second injection. It is usual to test for antibodies to hepatitis B in people who work in high-risk occupations because antibody titres can vary and some individuals may require extra doses of vaccine. It has been argued that if antibody titres are low, an infection will effectively act as a booster, giving adequate protection in view of the long incubation period for hepatitis B.¹⁰

Oral polio vaccine (OPV) In countries with a successful vaccination programme, polio has been virtually eliminated. When health systems break down or when a country is too poor to maintain childhood vaccination programmes, polio becomes a problem. This was witnessed in the early 1980s, when political problems in the old eastern bloc countries resulted in a resurgence of the disease. Primary immunisation will give protection for 10 years and adult travellers to many developing countries would be advised to obtain a booster.
One potential danger associated with OPV is that live vaccine is excreted in the faeces and there have been a few reports of individuals contracting vaccine-induced poliomyelitis from those who have received OPV. At most risk are the immunosuppressed or elderly and those who have not been previously vaccinated. For adults requiring primary immunisation, injectable inactivated polio vaccine should always be used because of a risk of vaccine-induced paralysis from OPV.

Typhoid Typhoid fever is caused by Salmonella typhi and is contracted from consuming contaminated food or water. The disease causes an initial gastrointestinal upset of diarrhoea or constipation but systemic infection may result, spreading to other organs with serious sequelae. The disease can be treated with antibiotics such as quinolones. Vaccination is recommended for travellers to areas where hygiene may be poor.
Despite being among the most widely administered vaccines, the risk of travellers contracting typhoid is low. In many countries the risk can be as low as one in 30,000, but in India, sub-Saharan Africa and parts of South America it can rise to one in 3,000.¹⁰ An additional consideration is that vaccination probably only gives, at best, 70 per cent protection against the disease and some studies have indicated that it may be even lower.¹¹ Furthermore, most trials have been performed on local populations in countries such as Nepal and the benefit for travellers from industrialised countries has not been fully defined.
The old whole cell vaccine is no longer used because the modern polysaccharide vaccine is associated with fewer adverse effects. It is also convenient, requiring just a single dose in advance of travel. The oral vaccine contains a short-lived mutant strain of S typhi but is used less because it has a complex dosing schedule resulting in problems with compliance.

Diphtheria and tetanus In both diseases, a toxin produced by the organisms is responsible for pathological damage. Vaccination is given during childhood using adsorbed toxoid but immunity begins to wane after 10 years. In the UK, it is advisable to have booster injections against tetanus every 10 years. Diphtheria has been virtually eliminated in many countries because of childhood vaccination schedules, so boosters are not routinely performed. In poorer countries, a similar situation to that described for polio can exist, where the childhood vaccination programme has broken down and diphtheria is a potential danger. For tourists on short stays to such destinations, vaccination against diphtheria is not usually necessary. On longer stays, particularly if there will be contact with the local population, boosters for adults over 20 years of age would be recommended. It is important that adults and children over six years of age receive an adult formulation of diphtheria vaccine which contains a lower dose than that used for younger children.

Yellow fever Yellow fever is a dangerous arboviral disease which is endemic in parts of Africa and South America. Yellow fever remains one of the few diseases for which a vaccination certificate is required for entry into some countries, although certificates may only be needed if entering from a yellow fever-endemic area. The vaccine is live freeze-dried, cultured on chick embryos and can only be supplied by registered yellow fever centres. This is partly historical because the vaccine can be sensitive to poor storage conditions and refrigeration equipment must be of a high standard. It is relatively easy for GPs to become yellow fever centres and increasing numbers are now registered. Once reconstituted, the vaccine must be used within a few hours.
A yellow fever vaccination certificate is not valid until 10 days after vaccination, so good planning is essential. Even if a certificate is not required for entry, the vaccine should be given if the disease is a risk. It should not be given to children under the age of six months because of a potential risk of encephalitis. Travel should be delayed, if possible, until infants are over 12 months of age, although most countries will allow exemption of a certificate for children younger than 12 months. Although yellow fever is theoretically contraindicated in pregnancy, no foetal malformations have been reported and the benefits may outweigh the risks.

Tuberculosis Tuberculosis is of greatest risk to travellers working or living with local populations in developing countries. Until the 1980s, most children in the UK were vaccinated with BCG (Bacillus Calmette-Guérin) at the age of 12. In more recent years, some health authorities have stopped carrying out this programme so that some younger adults have no immunity.
There are a number of problems associated with routine use of BCG in travel vaccination. First, it is important that individuals are tested for immunity before the vaccine is given because of a danger of an exaggerated immune response. This is complicated by the fact that reactions to the Mantoux/PPD (tuberculin purified protein derivative) skin test may be lost in later life despite immunisation. In addition, it takes two months following the BCG vaccine for immunity to develop. Another problem is that, while BCG gives an adequate response in young adults and children, whether immunity is conferred to older adults is a matter of debate. It has been claimed that BCG does not actually prevent infection, but helps prevent complications and disease spread.¹² In practice, vaccination clinics would mainly consider testing those at most risk, eg, people living in high-risk areas, especially where multidrug resistance is common, and those have not been previously vaccinated.¹³

Meningitis Meningococcal infection can be contracted in both industrialised and developing countries. In the UK, recent localised outbreaks have been of particular concern among young adults attending colleges. The strains of Neisseria meningococci which have been most frequently responsible for infection in Europe are of the serogroups B and C, whereas in other regions, such as Africa, serogroups A, C, Y and W135 are more common. In Africa, there is a "meningitis belt" extending from Mauritania to Ethiopia ¹⁴ in which an increased incidence of meningitis A can be expected during the dry season (December to June). Epidemics can occur almost anywhere in the world, and are often associated with dry seasons. There is greater risk of infection where many people are living in close proximity. For instance, during Haj pilgrimages to Mecca, serious outbreaks of meningitis have been reported in recent years. It is now an entry requirement to Saudi Arabia that those attending the Haj must possess a vaccination certificate against meningitis. Therefore, those travellers most commonly requiring vaccination are visitors to certain parts of Africa, to areas where an epidemic has been reported, or those planning to live in close proximity to local populations.
The vaccine currently available in the UK is effective against the A and C strains only and gives protection for three to five years. The C component is not effective in young children. This vaccine may not be adequate for protection in some situations, eg, during the Haj some pilgrims may have developed the W135 strain of meningitis. A new conjugate vaccine against the C strain is being employed in a childhood vaccination programme, but it gives no protection against other forms and the polysaccharide vaccine may need to be given in addition. If the conjugate form is given first, an interval of one month should be left before giving the polysaccharide form. This is because of a reduced response to the conjugate vaccine and an increased incidence of side effects. If the polysaccharide form has already been given, then a six-month interval should be left, although a two-week gap is adequate for children under five.

Rabies Rabies has an almost 100 per cent fatality rate so, despite the fact that only an extremely small number of travellers have ever contracted the disease, pre-exposure vaccination is an important consideration for those at risk. Rabies is transmitted by the bite of any mammal and is only completely absent in a few countries: the UK, Australia and Canada. In most industrialised countries where there is effective control of dogs and other mammals that might carry the disease, the risk of rabies is low and pre-exposure vaccination is unnecessary. In developing nations where control policies cannot be effectively enforced, the risk of being bitten by a mammal carrying rabies might be considerable. For instance, in recent years, there has been a particular problem of poor control of stray dogs in Nepal. Therefore, travellers visiting countries in Africa, Asia and South America for longer than a month may be advised to have pre-exposure vaccination.
Individuals must be aware that if they are bitten by an animal that may be carrying rabies, medical advice and post-exposure treatment must be sought immediately, even if they have had rabies pre-exposure vaccination. People often ask why they should bother with pre-exposure vaccination if such treatment is necessary. The main reason is that, in many parts of the world, post-exposure treatment cannot be assured. In addition, pre-exposure vaccination may "buy time" for those at a distance from medical help, and treatment is simpler in vaccinated individuals.
Treatment for rabies consists of immunoglobulins followed by a course of vaccinations of the same type used for pre-exposure. The immunoglobulins are sometimes unavailable and there is currently a world-wide supply problem. The modern human diploid cell vaccine is very different to the older type that required a series of painful abdominal injections. However, in some countries, only the older vaccine can be obtained.
The diploid vaccine is only available on the NHS for people with occupational risks, eg, veterinary surgeons, and the course of three subcutaneous injections can cost almost £100. Vaccination clinics often offer cheaper vaccines given by the unlicensed intradermal route which requires 0.1ml instead of the usual 0.5ml. Furthermore, for travellers at lower risk, a two- rather than three-dose schedule may be offered. There is a further unlicensed regimen which involves multiple intradermal injections at different sites for when vaccination is required at short notice.
Reactions to rabies vaccine are relatively frequent; around 5 per cent of recipients develop a type 3 (immune complex) systemic hypersensitivity which consists of an urticarial rash and malaise. Local reactions are reported in up to 10 per cent of individuals.

Japanese encephalitis Japanese encephalitis is an arboviral infection which is rare in travellers. Travellers at greatest risk are those on trips lasting longer than two to four weeks, and those visiting certain rural areas in Asia during the monsoon season, particularly pig breeding regions because pigs are important intermediary vectors for the disease.
Japanese encephalitis vaccine is currently unlicensed in the UK and a full course is expensive. The main limitation of the vaccine is a high incidence of both local and system adverse drug reactions. Local reactions have been reported in as many as 30 per cent of individuals vaccinated. Systemic reactions, including angioedema and urticarial rash, occur in one in 1,000 people but may be delayed for up to two weeks following injection.12 Therefore, it is advised that individuals are observed for 30 minutes after injection and that the course is completed 10 days prior to departure in order to identify these problems.
Studies in children in Asia have indicated that a reasonable response is obtained after two injections. However, studies in US travellers demonstrated that only 30 per cent of individuals had adequate levels of antibody after the second dose, so a full three-dose schedule is now recommended.¹²

Tick-borne encephalitis Tick-borne encephalitis is present in many parts of Europe, except for Portugal and the Benelux countries, and has the highest incidence in the Baltic regions. It is contracted through bites from ticks that thrive best in clearings in wooded areas. Vaccination is advisable for forestry workers and travellers planning to trek extensively in the countryside.
A tick-borne encephalitis vaccine is now licensed in the UK and is likely to be available in early 2001. In the interim, a vaccine can be obtained on a named patient basis from Baxter Healthcare.

FURTHER READING

1. Department of Health. Health Information for Overseas Travel 2000. London: Stationery Office; 2000.
2. Salisbury D, Begg N, editors. Immunisation against infectious diseases. London: Stationery Office; 1996.
3. Kassianos GC. Immunisation: childhood and travel health. Oxford: Blackwell Science; 1998.

Dr Goodyer is director of pharmacy practice research at King's College London, and superintendent of Nomad Travel Pharmacy

REFERENCES