Safety of Typhim Vi Vaccine in a Postmarketing Observational Study

Leonard C. Marcus VMD, MD, James E. Froeschle MD, David R. Hill MD, DTM&H, Martin S. Wolfe MD, Diane Maus RN, Bradley Connor MD, Alberto M. Acosta MD, PhD, Edward R. Rensimer MD, Alan Roberts MD, Kenneth Dardick MD
DOI: http://dx.doi.org/10.1111/j.1708-8305.2007.00158.x 386-391 First published online: 1 November 2007

Abstract

Background Typhoid fever is endemic in many parts of the world. In the United States, nearly three quarters of all cases are contracted by persons who traveled to regions with endemic disease. Typhim Vi, a vaccine containing the purified cell surface Vi polysaccharide of the Salmonella enterica serovar Typhi, was developed to provide protection against typhoid fever. We present the results of the largest safety study of this Vi vaccine to date.

Methods This open‐label, descriptive study assessed safety and reactogenicity following the Vi vaccine administration. Coadministration of other vaccines (at separate sites) was permitted, consistent with clinical practice. Participants aged 2 years or older with no known sensitivities to any vaccine component, who received the Vi vaccine, according to label directions, at a participating travel clinic, were eligible to participate. Information was collected on concurrent medications and medical conditions. The occurrence of solicited injection site reactions and systemic reactions was recorded on diary cards for 7 days following vaccination, along with any unsolicited medical events. Serious adverse events were reported for 30 days postimmunization.

Results A total of 1,204 participants (mean age: 37.2 y, range: 2–82 y, 55% female) were enrolled into the study, and 1,111 completed the 7‐day follow‐up. The most common solicited reactions were injection site pain [850 of 1,111 (76.5%)], tenderness [838 of 1,111 (75.4%)], and muscle aches [434 of 1,111 (39.1%)]. Fever was reported in 18 (1.6%) of 1,111 participants. Coadministration of other common travel vaccines did not affect reactogenicity profiles, except for an increase in the Vi vaccine injection site redness when two vaccines were administered in the same limb.

Conclusions The Vi vaccine was well tolerated in an unselected population, aged 2 to 82 years, presenting to a travel clinic for vaccination.

Typhoid fever is endemic in developing nations where poor sanitation and contaminated water supplies allow the spread of Salmonella enterica serovar Typhi, a highly adapted, human‐specific pathogen. The disease course generally begins with flulike symptoms, with increasing levels of fever; most cases involve gastrointestinal symptoms, either constipation or diarrhea. A lack of specific signs may make clinical diagnosis difficult. Complications, including gastrointestinal perforation or hemorrhage, shock, anemia, and meningitis, affect 10% to 15% of patients and may result in fatal outcomes. 1 World Health Organization data indicate that approximately 200,000 persons, mostly children, die each year from complications due to typhoid fever. 2 In developed nations, typhoid fever is most common in travelers returning from areas with endemic disease, but spread among traveler contacts may result in localized outbreaks. 1

Prevention and control of typhoid fever require hygienic measures, including improved sanitation and access to clean drinking water, and vaccination. 1 Vaccination can be considered for travelers to at‐risk areas of the Indian subcontinent, Africa, South‐East Asia, Central America, and South America. 1,3–6 In a recent study among travelers who visited a single country with high levels of endemic disease, 27% of cases began during a stay of 3 weeks or less, indicating that vaccination should be based on risk activities rather than just the length of stay. 7 Currently in the United States, two types of vaccine are recommended for use: a live, attenuated oral vaccine and the Vi parenteral polysaccharide vaccine. 3 The efficacy of parenteral polysaccharide vaccine has been demonstrated in clinical trials in Nepal, South Africa, and China. 8–10 Typhim Vi, Typhoid Vi Polysaccharide Vaccine (sanofi pasteur) for intramuscular use, is licensed in the United States and in more than 80 other countries for use in persons aged 2 years or older. We present the results of the largest safety and reactogenicity study of the Vi vaccine to date, which was conducted under normal clinical conditions at 11 travel clinics in the United States.

Methods

Study design

This is an open‐label, single‐group, descriptive trial to assess safety and reactogenicity following vaccination with the Vi vaccine (0.5 mL intramuscular injection into the deltoid muscle) at 11 travel clinics in the United States. All patients who received the Vi vaccine were invited to participate in this safety study. Informed consent was obtained before enrollment. Information was collected regarding the participants’ health status, any concomitant medications, and the number and type of other vaccines administered concomitantly with the Vi vaccine. Solicited reactions and unsolicited adverse events (including serious adverse events) were collected by use of a patient diary for 7 days. A second diary was used to capture serious adverse events for days 8 to 30 postvaccination. All subjects who reported local or systemic reactions that were unresolved at day 7 or that resulted in absence from work or school, loss of sleep, physician visit, or hospitalization were contacted by telephone and additional information was obtained to clarify the adverse event.

Outcome measures

The presence of Typhim Vi injection site reactions of redness, redness with a diameter greater than 1 inch, swelling or hardness, swelling with a diameter greater than 1 inch, tenderness to the touch, pain, or soreness was solicited. Injection site reactions were not solicited for any concomitant vaccines, and all reported injection site reactions are relative to the Vi vaccine injection site unless otherwise specified. Solicited systemic reactions collected were fever >100°F, rash, facial swelling, itching, hives, wheezing, joint pain, muscle aches, and headache.

At the time of vaccination, the site of the Typhim Vi injection was recorded on the diary card for the participant’s reference. Participants did not grade reaction intensity; instead, an adverse event was categorized as “severe” if it resulted in absence from school or work, loss of sleep, physician visit, or interference with the activities of daily living. Serious adverse events were defined, consistent with US Food and Drug Administration regulations, as events resulting in death, hospitalization or prolongation of hospitalization, permanent disability, or congenital anomaly or events that required medical intervention to prevent the preceding outcomes. Serious adverse events were assessed by investigators as to relationship to the study vaccine. Adverse events were collected and coded using COSTART.

Statistical analysis

The planned sample size was 1,000 evaluable participants, which would ensure a 95% probability of detecting a reaction occurring at a rate of 1/300 or greater. p Values were calculated using the chi‐square test (two‐sided alpha) to compare between‐group differences in the percentages of participants with solicited reactions and unsolicited adverse events, by the number of injections received; preexisting conditions (immunocompromised, asthma, cardiovascular disease, diabetes, and arthritis); concomitant therapies; and concomitant receipt of polio, yellow fever, diphtheria–tetanus, or hepatitis vaccines.

Results

Participants and vaccines

A total of 1,204 participants were enrolled into the study, of whom 1,111 (92%) completed the study. The mean age was 37.2 years and the range 2 to 82 years. Additional vaccines (up to six, but most typically one to three) were administered during the same clinic visit to 977 (88%) of 1,111 participants. The most commonly administered concomitant vaccines were hepatitis, tetanus–diphtheria, and yellow fever vaccines (Table 1). Relatively few participants reported specific underlying medical conditions (Table 1). All reported reactions resolved by day 7 following vaccination.

View this table:
Table 1

Participants’ demographic and baseline information: safety population

Information
Total participants enrolled, N1,204
 Lost to follow‐up, n (%)83 (7.5)
 Voluntary withdrawal, n (%)7 (0.6)
 Noncompliance with protocol, n (%)3 (0.2)*
Completed 7‐d follow‐up, n (%)1,111 (92.3)
Sex, n (%)
 Male500 (45.0)
 Female611 (55.0)
Race, n (%)
 Caucasian888 (79.9)
 African American77 (6.3)
 Asian88 (7.9)
 Hispanic33 (3.0)
 Other22 (2.0)
 Unknown3 (0.3)
Most common underlying health conditions, n (%)
 Cardiovascular disease 36 (3.2)
  Hypertension28 (2.5)
 Neurological disorders§ 21 (1.9)
  Depression11 (1.0)
 Asthma13 (1.2)
 Arthritis7 (0.6)
 Hypothyroidism7 (0.6)
 Immune suppression6 (0.5)
 Allergies5 (0.5)
Coadministered vaccines (type), n (%)
 Hepatitis A, B, or AB combination761 (68.5)
 Tetanus–diphtheria372 (33.5)
 Yellow fever290 (26.1)
 Polio260 (23.4)
 Meningococcal92 (8.3)
 Measles–mumps–rubella31 (2.8)
 Rabies26 (2.3)
 Japanese encephalitis17 (1.5)
 Pneumococcal13 (1.2)
 Lyme2 (0.2)
 Tetanus–diphtheria–pertussis1 (0.1)
Number of coadministered vaccines, n (%)
 0129 (11.6)
 1333 (30.0)
 2335 (30.2)
 3217 (19.5)
 480 (7.2)
 513 (1.2)
 64 (0.4)
  • * The three noncompliant were all 1 year of age.

  • Reported in four (0.4%) or more participants. Gastrointestinal disease was reported in three participants; anxiety, arrhythmia, arteriosclerosis, colitis, ulcerative colitis, ileitis, myalgia, osteoporosis, and sinusitis were each reported in two participants; no other concurrent condition was reported in more than one participant.

  • Includes a history of one or more of the following: hypertension, arrhythmia, angina pectoris, cardiomyopathy, arteriosclerosis, coronary artery disease, atrial fibrillation, myocardial infarction, palpitations, and tachycardia.

  • § Includes a history of one or more of the following: depression, convulsions, anxiety, myalgia, malaise, and hyperkinesia.

Injection site reactions

The most common injection site reactions were pain and tenderness. Compared to those who received only Vi vaccine, participants who received the Vi vaccine plus one or more additional vaccinations (Table 2) had no increase in reactions with multiple injections for any reaction, except redness at the Vi injection site in those who received Vi vaccine plus one or more vaccinations in the same arm [24 of 129 (18.6%) vs 101 of 356 (28.4%) p = < 0.01].

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Table 2

Number (%) of solicited injection site reactions, systemic reactions, and overall unsolicited adverse events within 7 days of vaccination, by number of coadministered vaccines

Number of concomitant vaccinesAny (N = 1,111), n (%)0 (n = 129), n (%)1 (n = 333), n (%)2 (n = 335), n (%)≥3 (n = 314), n (%)p Value *
Any Typhim Vi injection site reaction980 (88.2)113 (87.6)301 (90.4)289 (86.3)277 (88.2)0.42
 Redness244 (22.0)24 (18.6)73 (21.9)68 (20.3)79 (25.2)0.36
  Larger than 1 inch45 (4.1)7 (5.4)13 (3.9)13 (3.9)12 (3.8)0.88
 Swelling or hardness270 (24.3)34 (26.4)82 (24.6)78 (23.3)76 (24.2)0.92
  Larger than 1 inch65 (5.9)6 (4.7)14 (4.2)25 (7.5)20 (6.4)0.29
 Tender to touch838 (75.4)99 (76.7)248 (74.5)247 (73.7)244 (77.7)0.64
 Pain or soreness850 (76.5)100 (77.5)267 (80.2)245 (73.1)238 (75.8)0.19
Any solicited systemic reaction or unsolicited adverse reaction 589 (53.0)65 (50.4)177 (53.2)179 (53.4)168 (53.5)0.94
Solicited reactions
 Fever >100°F18 (1.6)1 (0.8)4 (1.2)8 (2.4)5 (1.6)0.53
 Rash24 (2.2)1 (0.8)9 (2.7)8 (2.4)6 (1.9)0.54
 Swelling (face area)25 (2.3)3 (2.3)9 (2.7)10 (3.0)3 (1.0)0.25
 Itching61 (5.5)4 (3.1)20 (6.0)22 (6.6)15 (4.8)0.41
 Hives8 (0.7)1 (0.8)3 (0.9)2 (0.6)2 (0.6)0.97
 Wheezing16 (1.4)3 (2.3)5 (1.5)5 (1.5)3 (1.0)0.75
 Joint pain124 (11.2)18 (14.0)36 (10.8)38 (11.3)32 (10.2)0.73
 Muscle aches434 (39.1)47 (36.4)131 (39.3)134 (40.0)122 (38.9)0.92
 Headache220 (19.8)20 (15.5)65 (19.5)57 (17.0)78 (24.8)0.05
One or more unsolicited adverse events 148 (13.3)16 (12.4)44 (13.2)51 (15.2)37 (11.8)0.62
  • * Chi‐square test, comparing reaction rates for those receiving zero, one, two, more than or equal to three concomitant vaccines.

  • Recorded as “other” on the day 0 to 7 diary card.

Receiving an analgesic was associated with reduced rates of injection site redness [3 of 50 (6.0%) vs 244 of 1,061 (23.0%); p < 0.01] and of pain or soreness [29 of 50 (58.0%) vs 850 of 1,061 (80.1%); p < 0.01].

Systemic reactions

The most common systemic reactions were muscle aches and headaches (Table 2). Receipt of three or more concomitant vaccines was associated with a higher rate of headache [78 of 314 (24.8%) vs 142 of 797 (17.8%); p = 0.01].

As expected, participants with specific preexisting conditions were more likely to report symptoms consistent with their underlying disease compared with the general study population. Participants with a history of asthma were more likely (p < 0.01) to report wheezing [9 of 69 (13.0%) vs 16 of 1,042 (1.5%); p < 0.0001]; those with arthritis were significantly more likely to report joint pain [5 of 7 (71.4%) vs 124 of 1,104 (11.2%); p < 0.0001]. Participants with a history of diabetes were significantly less likely to report any injection site or systemic reaction and, specifically, injection site pain (6 of 17 vs 838 of 1,111), tenderness or soreness (6 of 17 vs 830 of 1,111), and muscle aches (1 of 17 vs 434 of 1,111; all p≤ 0.05).

Severe reactions

Reactions categorized as severe were reported in 126 (11%) of 1,111 participants, of whom 5.9% reported interference with daily living, 3.2% loss of sleep, 1.5% absence from work or school, and 0.7% a physician visit. Injection site pain and muscle ache or joint pains were the reactions most likely to result in one of these consequences (Table 3).

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Table 3

Number (%) of common unsolicited adverse events (reported by ≥10 participants) within 7 days and severe reactions* within 30 days following vaccination

Total, N1,111
Any unsolicited adverse event, n (%)148 (13.3)
 Malaise32 (2.9)
 Dizziness17 (1.5)
 Pain17 (1.5)
 Insomnia15 (1.4)
 Nausea13 (1.2)
 Myalgia11 (1.0)
 Fever10 (0.9)
 Headache10 (0.9)
Any severe reactions*, n (%)126 (11.3)
 Absence from work or school17 (1.5)
  Fever or chills4 (0.4)
  Muscle ache or joint pain8 (0.7)
  Injection site pain6 (0.5)
  Other 11 (1.0)
 Loss of sleep36 (3.2)
  Hives, itching, or rash4 (0.4)
  Muscle ache or joint pain2 (0.2)
  Injection site pain14 (1.3)
  Other 26 (2.3)
 Physician visit8 (0.7)
  Fever or chills1 (0.1)
  Hives, itching, or rash2 (0.2)
  Other 11 (1.0)
 Interference with activities of daily living65 (5.9)
  Fever or chills3 (0.3)
  Hives, itching, or rash2 (0.2)
  Muscle ache or joint pain27 (2.4)
  Injection site pain39 (3.5)
  Other 26 (2.3)
  • * Defined as a reaction that resulted in absence from school or work, loss of sleep, physician visit, or interference with the activities of daily living.

  • Includes respiratory infection, gastrointestinal complaints, dizziness, wheezing, anxiety, leg cramps, tooth disorder, wart, chest tightness, and poison ivy.

Unsolicited adverse events

Unsolicited adverse events were reported by 148 (13.3%) of the 1,111 participants. The most common unsolicited adverse events were malaise, dizziness, and pain (Table 3).

Serious adverse events

Two serious adverse events were reported, both within 7 days of vaccination; there were no serious adverse events reported for days 8 to 30. Five days after receiving the Vi vaccine, inactivated polio vaccine, and hepatitis A vaccine, a 43‐year‐old man with a history of multiple drug and environmental allergies developed generalized urticaria accompanied by pruritus. The subject was treated with diphenhydramine and was not hospitalized. The investigators assessed this event as possibly related to vaccination. Another participant developed severe Campylobacter diarrhea, which was considered unrelated to study vaccine by the investigators.

Discussion

Adverse reactions reported among 1,111 persons aged 2 to 82 years, who presented to a travel clinic and received the Vi vaccine, were consistent in frequency and character with those commonly reported following any prospective vaccine study using diary cards to solicit adverse reactions. The majority of participants reported some degree of injection site or systemic reactions, but fewer than 6% experienced any meaningful interference with their usual activities of daily living, and fewer than 1% sought medical treatment for these reactions. No adverse reactions were reported that were new or unexpected in light of participant medical histories, product labeling, and previously published studies of the safety of these vaccines.

In keeping with current recommendations for travelers outside the United States, 3–7 the majority of participants in this study received one or more additional vaccines recommended for travelers, such as hepatitis, tetanus–diphtheria, yellow fever, or inactivated polio vaccines. Vi vaccine injection site redness was more likely when two or more vaccines were administered in the same limb, compared with the administration of the Vi vaccine alone. No clinically meaningful patterns were apparent in the systemic reactogenicity profiles.

Findings in participants with underlying medical conditions or who were receiving concomitant medications did not show unexpected results. Participants with preexisting arthritis were more likely to report joint pain and those with preexisting asthma were more likely to report wheezing compared with the full study populations, consistent with the symptoms that characterize those conditions. Further, those receiving concomitant analgesic therapies were less likely to report injection site pain or tenderness, as might be expected, given the action of those agents.

The reactogenicity profile observed in our study was consistent with that reported in the product prescribing information and in subsequent clinical trials and reviews. 11–13 Compared to the current prescribing information, our participants reported somewhat more injection site pain and less injection site tenderness. 14 As would be expected, the findings in our study appear more favorable than those reported by Begier and colleagues in their analysis of 1990 to 2002 postmarketing Vaccine Adverse Event Reporting System (VAERS) reports. 15 They reviewed 321 reports for Typhim Vi vaccine, of which 7.5% described death, hospitalization, permanent disability, or life‐threatening illness (including anaphylaxis); this difference in results is consistent with differences in data collection as VAERS is a voluntary passive reporting system and thus biased toward reporting of serious, severe, or disabling reactions to vaccines or biologics products.

In conclusion, we found that the Vi vaccine was generally well tolerated by healthy persons aged 2 to 82 years under the usual conditions of vaccination at US travel clinics. No preexisting medical condition or medication was identified as a risk factor for postvaccination adverse events, and coadministration of up to six additional vaccines did not affect reactogenicity, except for an increase in injection site redness when two vaccines were administered to the same limb.

Declaration of interests

J. E. F. and D. M. have been employees of sanofi pasteur at the time of the study. Otherwise, the authors state that they have no conflicts of interest.

Acknowledgments

This study was funded by sanofi pasteur, Inc.; Lisa DeTora, PhD, Daniel Gordon, MD, and Michael D. Decker, MD, MPH, provided guidance and editorial support during the writing of this manuscript. J. Shipley, J. Bellanti, S. McDevitt enrolled participants into the study and made study assessments. W. Edward Miller, Rhonda Hoffman, and Steven Schmaltz, PhD of Partners in Research, Louisville, KY, participated in data collection and analysis.

Footnotes

  • Results of this study were presented in part at the 8th Conference of the International Society of Travel Medicine, May 7–11, 2003, New York.

References

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