Journal of Infection (I99:0; 25, 63-66

E x p e r i e n c e w i t h Vi t y p h o i d c a p s u l a r p o l y s a c c h a r i d e vaccine in the U.K. W. S. G. Arnold,* A. W. Harcus,t J. St Clair Roberts*~ and A. E. WardT Mdrieux U.K. Ltd, Clivemont House, Clivemont Road, Maidenhead, Berkshire SL6 7B U and t Medicos, 79 Beverley Road, Kingston upon Hull HU3 IXR, U.K. Accepted for publication 25 January I992

Summary Adult volunteers were immunised with a single dose of typhoid Vi capsular polysaccharide vaccine. After immunisation, 96 % of the Io3 subjects seroconverted and 94 % had antibody levels above the protective threshold. Systemic reactions were uncommon, local reactions were mild and transient. Introduction

T y p h o i d fever is still endemic in many parts of the world, where it may be encountered by travellers from non-endemic regions such as the U.K. T h e annual incidence of typhoid fever in England and Wales remains about I5o cases, 8o % of which are acquired overseas, mainly from the Indian subcontinent. 1 Residents of this country are at low risk of exposure to typhoid and other enteric fevers unless they are contacts of a disease carrier or are at occupational risk. However, visitors travelling outside Europe may still be exposed to the risk of typhoid fever, despite careful attention to personal hygiene, and it is usually for these individuals that immunisation may offer useful additional protection. Currently available parenteral vaccines confer between 5I and 66% protection. 2 These inactivated whole-cell vaccines do, however, cause significant systemic and injection site reactions which have limited the implementation of national immunisation programmes. Furthermore, reactions are more frequent and may be more severe in recipients who have received previous doses and those aged over 35 y e a r s ) Vi antigen is the capsular polysaccharide of Salmonella typhi. Apart from occasional strains of S. paratyphi C, S. typhi is the only member of the genus Salmonella to possess a polysaccharide capsule. Two large-scale field trials have evaluated the protection conferred after a single 25 mcg dose of typhoid Vi capsular polysaccharide vaccine. 4,5 These demonstrated efficacies of between 58 %, 8I % and 74% respectively, with a low incidence of side effects. Further work has shown that raised titres of Vispecific antibodies persist for at least 3 Years.6 ~: Author to whom all correspondence should be addressed. oI63-4453/9e/o4oo63 +04 $o3.oo/o

© ~992 The British Society for the Study of Infection

64

w.s.G.

ARNOLD

ET AL.

Patients and m e t h o d s

We conducted an open study among healthy adult volunteers. A history of previous immunisation against typhoid fever was sought, and those i m m u n i s e d during the previous 5 years were excluded, as were those who had at any time experienced severe reactions after typhoid vaccine. At study entry a IO ml venous blood sample was drawn, the serum separated and stored at - 2 o °C until assay. Volunteers were i m m u n i s e d with a single liquid dose (o'5 ml) containing 25 meg of Vi polysaccharide (PasteurMerieux), administered by deep subcutaneous or intramuscular injection. After immunisation, subjects were asked to complete a questionnaire daily for IO days. Serum samples were analysed by radio-immunoassay (RIA); seroconversion was defined as an increase in specific antibody to Vi I> o'I5 mmol/1 serum. 7 T h e assay sensitivity was o.oi mmol/1, and protection defined as an antibody titre ~> I'5 mmol/1 (Robbins JB, unpublished data). Results

One h u n d r e d and seven subjects were recruited. Data concerning side effects were available from IO4 subjects, and serum samples for analysis from lO3. Fifty-eight males, mean age 28.8 years (standard deviation, S.D., _ IO'2 years) and 49 females, mean age 35"7 years (S.D. + I I'O years) were entered. Eight subjects had received typhoid vaccine previously. Serological responses

Before immunisation, 33 subjects had detectable anti-Vi antibodies above the protective threshold (~> I'5mmol/1). Of the six subjects whose postimmunisation antibody levels were < I'5 mmol/1, four had seroconverted; and of the 33 whose pre-immunisation levels were above the protective threshold (~> I'5 mmol/l), 32 (97%) seroconverted as defined by a rise in antibody level of ~> o'15 mmol/1. Of all subjects 96"I % seroconverted and 94"2 % had post-immunisation titres above I'5 mmol/1 (Table I). Clinical responses

Subjects were asked to report any possible side effects experienced at any time during the Io days following immunisation. Reactions were recorded in 92 of the lO4 available diaries; 58 of these recorded reactions localised to the injection site, 3I had injection site and systemic reactions and three reported systemic reactions alone (Table II). T h e most frequently reported reaction was pain at the injection site, noted by 71 (69%). Of these, 5 4 % noted a m a x i m u m severity of tenderness, only on pressure. T h e mean duration of this s y m p t o m was 2"2 days (S.D. _ I'O days) with a m a x i m u m duration of 6 days. Injection site erythema was reported by 45 subjects (44%), the mean m a x i m u m diameter of erythema was 3o m m (range: 5-55 ram), lasting for a mean m a x i m u m of 2.i days (S.D. _+ I'I days). Swelling at the injection site was noted by I7 (I7 %) subjects, with a mean m a x i m u m diameter of 2"8 cm, for a mean duration of I'9 days (S.D. __+I'2 days).

Experience with typhoid Vi vaccine

65

I Serological responses after immunisation

Table

Numbers (%)

Pre n Seroconversion Geometric mean titre < I'5 retool/1 >~ I'5 mmol/1

(%)

n

-1-22 70 (68) 33 (32)

99

--

Post (%) (96)

4"25 6 97

(6) (94)

I I Reactions experienced by I o 4 vaccinees

Table Reaction/ symptom

Pain Erythema Swelling Local muscle ache Headache General aches Nausea Feverish Itching Others

Number

Per cent

Mean duration

Standard deviation

7I 45 I7 29

68 43 I6 28

2-2 2" I I'9 I'5

i,o I" i I-2 0'63

22

21

2"O

I'4

I4 11 8 5 15

I4 II 8 5 --

I'7 I"7 I'9 I'5" --

0"83 1.2 ----

* Median. Table

I I I Other symptoms noted by vaccinees

Symptom Respiratory tract symptoms Fatigue/lethargy Gastro-intestinal/diarrhoea Rash Paraesthesia/tingling Total

Number reporting 6 4 3 I I I5 (I4 %)

Subjects were asked to report any other symptoms noted after immunisation (Table III). There was no significant difference between the number of reactions seen in males and females (Chi squared, P > o'I), or the number of reactions seen in those who had and had not received previous typhoid vaccines. All of these reactions were self-limiting, with none requiring time off work, treatment or consultation with the subject's own doctor. 3

J I N 25

66

W. S. G. ARNOLD E T AL. Discussion

T h e significant reactions seen after inactivated whole-cell vaccines have limited their widespread usage; indeed in the W H O field trials, inability to work was reported in 23 % subjects, with significant fever observed in b e t w e e n 6"7 and 29 % individualsfl M o r e recently, several candidate t y p h o i d vaccines have emerged including orally administered inactivated whole-cell vaccines, oral live attenuated vaccines and the purified polysaccharide (Vi) vaccine used in this study. T w o large-scale placebo-controlled field trials 4'5 have been c o n d u c t e d in endemic regions in order to evaluate the protection conferred b y a single 25 mmol/1 dose of purified polysaccharide (Vi) vaccine. T h e s e took place in South Africa and Nepal at times when t y p h o i d fever was highly prevalent, with annual attack rates b e t w e e n 500 and I000/I00 000 population. T h e high disease attack rate provides exacting conditions in which to test the protection conferred by immunisation. 8 Protective efficacy was 5 5 - 7 0 % after 3 years follow up (unpublished data) which equates with the seroconversion rates seen in those subjects in w h o m serological responses were measured. 5 O u r results show that seroconversion rates in a British population not exposed to endemic t y p h o i d fever are > 95 %, and protective antibody levels are achieved in 94 %. T h e open design of this study does not permit comparison of reported reaction rates; however, the intensive surveillance over IO days was intended to detect all possible reactions regardless of triviality. T h e majority of reactions observed were mild and short-lived, none required treatment or interfered with d a y - t o - d a y activity. References

I. Department of Health. Immunisation against infectious disease. London: HMSO, I99O. 2. Levine MM, Ferreccio C, Black PE, Tucker CO, Germanier R. Progress in vaccines against typhoid fever. Rev Infect Dis I989; II (Suppl.): S 552-565. 3. Wellcome Medical Division. Protection and prevention 7th Ed. Crewe: The Wellcome Foundation, I984. 4. Klugman KP, Koornhof HJ, Gilbertson IT et al. Protective activity of Vi capsular polysaccharide vaccine against typhoid fever. Lancet 1987; ii : I I65-I 169. 5. Acharya IL, Lowe CV, Thapa R et al. Prevention of typhoid fever in Nepal with the Vi capsular polysaccharide of Salmonella typhi. N Engl J Med I987; 317: IIOI-IIO 4. 6. Tacket CO, Levine MM, Robbins JB. Persistence of antibody titres 3 years after vaccination with Vi polysaccharide vaccine against typhoid fever. Vaccine I988; 6: 3o7--3o8. 7. Tacket CO, Ferreccio C, Robbins JB et al. Safety and immunogenicity of two Salmonella typhi capsular polysaccharide vaccines. J Infect Dis I986; I54: 342-345. 8. Klugman KP, Vosloo H, Arntzen L, Koornhof HJ. Prevention of typhoid fever by single-dose capsular polysaccharide vaccination. Proceedings of the ist Conference of Travel Medicine. Berlin: Springer Verlag, I989.