Smallpox revaccination of 21000 first responders in Israel: lessons learned

Article Outline

• Summary
• Introduction
• Methods
• Results
  • Vaccine take
  • Cold chain
  • Side effects of vaccination
  • Serologic responses
  • VIG production
• Discussion
• Conclusions
• Acknowledgements
• References
• Copyright

Summary 

Objectives

Between July 2002 and April 2003, over 21000 individuals were revaccinated against smallpox by the Israeli Ministry of Health. The objectives of the campaign were to create an immunized core of first responders, to review vaccination techniques, and to produce vaccinia immune globulin (VIG).

Methods

The Lister strain of vaccinia virus was used at a concentration of approximately 10⁷ pock-forming units (PFU)/ml, and was administered by the multiple-puncture technique. The revaccinees were from varied ethnic backgrounds, almost all were aged 25–64 years, and all participants had been vaccinated against smallpox in the past.

Results

The proportion of clinical take was 66.1% (95% CI: 65.2%, 67.0%), similar to past vaccination programs when take also occurred in approximately two thirds of vaccinees. An antibody response occurred in 77.7% (95% CI: 74.8%, 80.6%) of all revaccinees: 94.4% (95% CI: 91.8%, 96.3%) of those with clinical take and 56.6% (95% CI: 51.3%, 61.8%) of those without clinical take. The most common side effects corresponded to symptoms of non-specific viral diseases, and only a few revaccinees reported serious side effects.

Conclusions

The campaign achieved all its basic goals and provided useful lessons for any mass-vaccination programs that might be necessary in the future.

Keywords: Smallpox revaccination, Vaccine take, Side effects, Serologic response, VIG production

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Introduction 

Between July 2002 and April 2003, the Israeli Ministry of Health revaccinated some 21000 medical personnel and other first responders against smallpox. The purposes of this limited campaign were: (1) to provide a future cadre of personnel capable of administering smallpox vaccine, investigating suspected smallpox cases, and evacuating and treating smallpox patients; (2) to review vaccination methods, since the routine vaccination of the civilian population was terminated in 1980; and (3) to obtain plasma rich in vaccinia antibodies (vaccinia immune globulin; VIG) for the treatment of defined smallpox vaccination complications. This report summarizes the highlights of the revaccination campaign, with particular emphasis on the clinical responses and side effects observed, and in correlation with the serologic responses of the revaccinees.

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Methods 

The vaccine used was the Lister strain of vaccinia virus, which was grown on chorioallantoic membranes of fertilized eggs, and which was produced by the Central Laboratories of the Israeli Ministry of Health.¹ The vaccine antigen concentration was 10⁷ pock-forming units (PFU)/ml of vaccinia virus, which was kept frozen at −80°C. Several vaccination methods were considered: jet injector, multiple puncture by lancet, multiple puncture by 23-gauge needle, and multiple pressure by lancet. As they were not available at the time, bifurcated needles were not used. After several alternative methods were explored, the technique chosen was inoculation by delivery of approximately 20μl of the vaccine suspension onto the vaccination site (the skin overlying the deltoid muscle) using a ‘helicopter’ pipette, followed by 15 brisk punctures with a 23-gauge needle (Figure 1).

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• Figure 1. 

  Helicopter pipette.

All revaccinees volunteered to participate in the campaign and included first responders such as nurses, physicians, laboratory technicians, pre-hospital emergency staff, police, firefighters, and military personnel. Most were Israeli government employees and other individuals working in the public sector. All declared they had been vaccinated in the past against smallpox, although only few presented written documentation of prior vaccination. Thorough examinations of all candidates were made for scars from prior smallpox vaccination (including at less conventional sites, such as the posterior thigh). In all cases of doubt regarding prior inoculation, the decision was made not to vaccinate.

Before being vaccinated, candidates were provided with a lecture, written materials, and a slide show describing smallpox, the vaccinia vaccine, contraindications to vaccination, and possible complications. Participants completed a questionnaire in which they provided demographic information and noted relevant medical conditions, particularly the presence of contraindications. The latter were identical to those described by the US Centers for Disease Control and Prevention (CDC),² and included eczema, past or present, in the candidate or a household member; other active widespread skin disease in the candidate or a household member; immunosuppression in the candidate or a household member; pregnancy in the candidate; and a life-threatening allergy to eggs. Women receiving vaccine were advised to practice birth control for one month following revaccination. Towards the end of the campaign additional contraindications were added according to subsequent CDC recommendations,³ such as underlying heart disease, selected autoimmune diseases, and the presence of a pregnant woman in the household.

Vaccine recipients were advised to keep the vaccination site uncovered under a sleeve, but were permitted to use a loose gauze dressing if necessary to protect clothing from oozing transudate. Persons providing direct patient care were advised to use a loose dressing at all times and to wash their hands after touching the vaccination site.

A 10ml blood sample was obtained from the first several hundred revaccinees prior to vaccination and again approximately 30 days later, at which time revaccinees were asked to undergo plasmapheresis or to donate a unit of blood from which plasma could be extracted.

Vaccine recipients reported local and systemic reactions via a questionnaire, which was completed 7 to 9 days after vaccination. Questionnaires were self-completed by medical professionals; in other cases, a physician or nurse from the revaccinee's institution, or from the local public health office, assisted in the completion of the questionnaire. Clinical ‘take’ (major response) was determined by the appearance of a blister, pustule, ulcer, or scab 7 or more days following revaccination. We recommended repeat revaccination to those without clinical take.

Serological studies were performed to determine antibody titer levels in the Health Ministry's Central Virology Laboratory using a modified microneutralization assay as described by Somekh et al.⁴ Contingency analyses were performed to measure the association between take and demographic variables as well as various side effects. The rate of side effects among first versus repeat revaccinations were also compared using Chi-square statistics. Kappa tests were performed comparing clinical take with paired serological measurements. Multivariate logistic analysis was used to analyze proportions of take for various institutions and batches of vaccine.

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Results 

A total of 21139 persons were revaccinated. Completed questionnaires were submitted to the Health Ministry's Departments of Epidemiology and Infectious Diseases for inclusion in a computerized database. The data in this report are based upon the 11471 questionnaires that were available for analysis. These questionnaires came mainly from civilian revaccinees, most of whom worked in the health sector. Based on the questionnaires 7456 revaccinees (65%) were women; almost all revaccinees (97%) were aged 25–64 years; 48.5% of the revaccinees were Israeli born and 27.5% came from the New Independent States (NIS) of the former Soviet Union and from other European countries. The age and origin distributions are shown in Table 1.

Table 1. Distribution of revaccinees by age and origin.

Origin	Age group (years)						Total
	1–24	25–34	35–44	45–54	55–64	65+
Israel	109	1436	1766	1730	487	35	5563 (54.7%)
NIS	46	606	710	521	258	14	2155 (21.2%)
All other European countries	9	64	155	431	306	32	997 (9.8%)
Africa	4	25	104	253	106	6	498 (4.9%)
Middle East	2	8	52	163	121	9	355 (3.5%)
South and Central America	0	16	59	108	61	5	249 (2.5%)
North America	2	20	56	91	51	9	229 (2.3%)
Asia	1	2	12	33	60	1	109 (1.1%)
Total	173 (1.7%)	2177 (21.4%)	2914 (28.7%)	3330 (32.8%)	1450 (14.3%)	111 (1.1%)	10155a (100%)

NIS, New Independent States of the former Soviet Union.

Vaccine take 

According to the questionnaires submitted, the proportion of clinical take was 66.1% (95% CI: 65.2%, 67.0%). There was no statistically significant difference in take between genders (p=0.60). Clinical take occurred in 66.4% (95% CI: 64.9%, 67.9%) of men and 65.9% (95% CI: 64.8%, 67.0%) of women. Except for those aged less than 25 years, the proportion of clinical take tended to increase with age (Figure 2). The proportion was 58.3% (95% CI: 56.3%, 60.3%) in revaccinees aged 25–34 years, 67.1% (95% CI: 66.0%, 68.2%) in those aged 35–54 years, and 71.1% (95% CI: 69.0%, 73.2%) in those aged 55 years and over. In the few revaccinees aged less than 25 years, clinical take averaged 76.9% (95% CI: 70.6%, 82.4%). The overall p-value of the Chi-square statistic was <0.0001.

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• Figure 2. 

  Major response (clinical take) by age group.

There were statistically significant differences in take as a function of birth country (p-value of the Pearson Chi-square statistic of <0.0001). The highest average proportion of take was recorded among revaccinees born in the NIS at 71.4% (95% CI: 69.4%, 73.3%); those born in South and Central America had the lowest recorded proportion of take, 51.4% (95% CI: 45.0%, 57.8%), but this group represented only 2.5% of revaccinees (Figure 3).

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• Figure 3. 

  Major response (clinical take) by origin.

The proportion of clinical take among repeat revaccinees was 58.4% (95% CI: 52.4%, 64.3%), significantly lower than among all initial revaccinees, and the p-value measured by the exact Fisher test was 0.009.

Cold chain 

Very different proportions of take were observed between institutions using the same lot of vaccine. Considering the three largest batches, which were administered to 94% of all revaccinees, in institutions where at least 20 of these doses were used, the proportion of take varied from less than 35% to greater than 70% (with a p-value for the Pearson Chi-square statistic of <0.0001 for each batch). It was discovered that in the institution with the lowest average proportion of take, the vaccine was delivered with cold packs, kept refrigerated, and then maintained at room temperature for the duration of the vaccination session. In contrast, in institutions with higher proportions of take, the vaccine was delivered on dry ice, kept frozen at −80°C and then stored on ice throughout the session. We also found that after the vaccine was defrosted, it had to be used within a 24-hour period in order to maintain the take level. The instructions regarding the cold chain were revised accordingly.

Side effects of vaccination 

Most recipients (n=9243 or 80.6%) reported local manifestations and/or systemic side effects. There was an association between the rate of local manifestations (other than those included in the definition of clinical take) and the proportion of take. Revaccinees without clinical take and repeat revaccinees exhibited substantially fewer local and systemic manifestations: 1781 (45.8%) of revaccinees without clinical take, and 83 (29.75%) of repeat revaccinees, exhibited at least one local and/or systemic side effect. These findings are summarized in Table 2, Table 3.

Table 2. Local and systemic manifestations with or without major response (clinical take).

CI, confidence interval.

Table 3. Local and systemic manifestations on first vs. repeat revaccination.

CI, confidence interval.

The most commonly reported side effects were those of non-specific viral diseases such as weakness, fatigue, nausea, headaches, chills, and joint and/or muscle pain. Revaccinees were particularly troubled by extensive local swelling and pain, and several sought medical care and even received antibiotic treatment. One female revaccinee was hospitalized with a diagnosis of cellulitis while in Jordan on a visit. There were 221 instances of inadvertent self-inoculation of vaccine and 17 instances of accidental spread of vaccine virus to a healthy household member. In one case, which resulted in generalized vaccinia, a household member undergoing immunosuppressive therapy was accidentally inoculated. This patient received vaccinia hyperimmune plasma and recovered.

Thirteen revaccinees experienced serious adverse events, defined by the need either for a visit to a clinic or emergency department, or for hospitalization. Of these 13, two exhibited generalized vaccinia, two suffered from erythema multiforme, and two suffered from optic neuritis. Other serious adverse events included a retinal branch vein occlusion, a perimyocarditis, a polymyalgia, a localized urticarial eruption, a paresthesia of the fingers, a case of herpes zoster, and a cervical lymphadenopathy. All except the patient with polymyalgia and one patient with erythema multiforme recovered or substantially improved.

Serologic responses 

A total of 825 paired samples (in which pre-vaccination and post-vaccination specimens were taken from the same person) were available for analysis of serological responses in revaccinees. Among the paired samples, a positive response of an antibody titer increase of at least four-fold between pre- and post-vaccination specimens was detected in 77.7% (95% CI: 74.7%, 80.6%) of revaccinees. There was a statistically significant difference in serological response between genders (p-value of Chi-square statistic=0.01). A positive serological response occurred in 71.8% (95% CI: 63.2%, 79.3%) of men and 81.9% (95% CI: 78.1%, 85.3%) of women. There was no significant difference in serological response as a function of age: the proportion was 77.8% (95% CI: 62.9%, 88.8%) in revaccinees aged 25–34 years, 81.5% (95% CI: 76.9%, 85.6%) for those aged 35–54 years, and 79.7% (95% CI: 73.7%, 84.9%) for those aged 55 years and over, with the overall p-value of the Chi-square statistic being 0.77.

Among revaccinees with clinical take, 94.4% (95% CI: 91.8%, 96.3%) had a positive serological response, compared with 56.6% (95% CI: 51.3%, 61.8%) for those without clinical take (Figure 4). This results in a kappa statistic of 0.40, which indicates a fair to moderate agreement between clinical take and antibody titer.

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• Figure 4. 

  Major response (clinical take) and serologic response.

The rate of side effects for those with a positive serological response was 63.5% (95% CI: 59.5%, 67.4%), and for those without a positive response it was significantly lower, 35.4% (95% CI: 27.7%, 43.7%), with an exact Fisher test p-value of less than 0.0001 (Table 4).

Table 4. Systemic side effects by major response (clinical take) and serologic response.

CI, confidence interval.

VIG production 

The plasma obtained from revaccinees was used to produce 2500 l of VIG, with a total protein concentration of between 4.5% and 5.5%, and an anti-vaccinia titer that exceeded 5000 neutralizing units/ml, as determined by an ELISA test.

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Discussion 

A smallpox vaccination campaign, in which 21139 first responders were revaccinated, was conducted in Israel more than two decades after the cessation of routine smallpox vaccination. The results show that the vaccine produced in Israel had a similar potency to that achieved over 40 years earlier when, as reported in 1961,⁵ the overall proportion of clinical take was also approximately two thirds. However while the proportion of take in the recent campaign equaled prior historical levels, it was considerably lower than the proportions of take recorded in the last US vaccination campaign, which began in 2002. The proportion of take in US vaccinees was 95% using 1×10⁸ PFU/ml undiluted vaccine,⁶, ⁷ and it was 81% with vaccine diluted at 1:10,⁶ the same concentration that was used in Israel.

There were several differences between the vaccination campaigns in the USA and Israel: the strains that were used (the NYCBOH strain in the USA and the Lister strain in Israel); the vaccine concentration (1×10⁸ PFU/ml in the USA and 1–2×10⁷ PFU/ml in Israel); the vaccination technique (a bifurcated needle in the USA and multiple puncture with a 23-gauge beveled needle in Israel); the inclusion of primary vaccinees in the US campaign (of over 450000 military vaccinees, 70.5% were naïve,⁷ while all participants in the Israeli campaign had been inoculated previously against smallpox); and the average time elapsed since the last vaccination (which was shorter in Israel).⁸

Balicer et al.⁹ showed that the use of a bifurcated needle was not a factor influencing the proportion of take in the Israeli smallpox vaccination campaign, and Frey et al.¹⁰ concluded that proportions of take did not differ significantly among vaccinees receiving 10⁸ PFU/ml as compared with those receiving 10⁷ PFU/ml. This conclusion is supported by the results of a study conducted by Couch et al.¹¹ showing that over a dose range of 10^6.2–10^8.2 PFU/ml there were no significant differences in vaccination success rates. The two factors that most probably did play a major role in lowering the proportion of take in Israel, as compared with that in the USA, were the levels of pre-existing antibodies among vaccinees and the average time since last vaccination, which are important determinants in the duration of protection against smallpox.¹², ¹³ Indeed we noted that pre-vaccination antibody titers were generally higher in revaccinees without clinical take compared to those with clinical take (data not shown). Similar conclusions were reached by Orr et al.¹⁴ in a study conducted on a sample of military revaccinees.

The rate of reported side effects was high, although serious side effects were rare and no life-threatening side effects occurred. The most troublesome side effects were the local manifestations of vaccination. The next most common side effects were those of non-specific viral disease, such as fever, malaise, and fatigue. As the revaccination campaign progressed there were fewer reports of minor side effects, as medical professionals refamiliarized themselves with the smallpox vaccination process and its accompanying problems. Nevertheless, if an emergency mass campaign were required, in which hundreds of thousands of citizens were to be vaccinated each day, health authorities would certainly find themselves inundated with complaints of side effects. The experience gained from this revaccination campaign points to the importance of adequate training and instruction, as well as the operation of vaccination information centers to ensure a continuous flow of information to medical personnel, vaccinees, and the public.

Generally, there was a good association in the revaccination campaign between clinical take and the appearance of antibodies, which were tested in a random subset of the revaccinees. The laboratory results showed antibody response in more than 94% of revaccinees with clinical take, and also in more than 56% of the tested revaccinees who did not have clinical take. However, the meaning of antibody response in terms of protection following exposure is unknown, and cannot be learned at this time. While for some specialists clinical take will continue to be the gold standard for smallpox vaccination success, others point to alternative measures, such as cellular immunity, as preferable criteria. A quantitative benchmark for protection against variola virus should be clarified in the future.

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Conclusions 

The campaign achieved its essential goals, which had been to revaccinate a cadre of first responders, to review vaccination techniques, and to obtain high-quality VIG. Nonetheless, Israeli public health officials are following with interest the development of new smallpox vaccines that might have fewer contraindications, result in fewer side effects, and gain a broader acceptance among medical professionals and the general public.

Finally, while the World Health Organization declared smallpox eradicated in 1979, we need to be aware that the risks of international bioterrorism that gave rise to Israel's 2002–2003 revaccination campaign oblige public health professionals the world over to be prepared, both medically and logistically, for the reappearance of smallpox in our time.

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Acknowledgements 

We acknowledge with thanks Bruce Warshavsky for his editorial assistance; Miriam Yosefine, Michael Takhman, Mark Bruk, and Yael Arbel for their work on data management and analysis; Ethel-Sherry Gordon for providing statistical analysis; Zvia Supiev and Marina Alkin for their laboratory technical assistance; Rina Buazov for her technical assistance; and Ruslan Gusinov for his work on the graphics.

Conflict of interest: No conflict of interest to declare.

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References 

1. Gerichter CH. Preparation of vaccine against smallpox in chorioallantoic membranes of chicken embryos. Jerusalem, Israel: Public Health Services, Israeli Ministry of Health; 1966;p. 36–41
   • View In Article
2. Rotz LD, Dotson DA, Damon IK, Becher JA; Advisory Committee on Immunization Practices. Vaccinia (smallpox) vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2001. MMWR Recomm Rep 2001;50(RR-10):1–25.
   • View In Article
3. Centers for Disease Control and Prevention (CDC). Supplemental recommendations on adverse events following smallpox vaccine in the pre-event vaccination program: recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep 2003;52:282–4 and 52(RR-7):1–16.
   • View In Article
4. Somekh E, Smetana Z, Tanay A, Dalal I, Babai I, Mendelson E. Determination of immunity to vaccinia virus using diluted, inactivated vaccinia vaccine solution for skin testing. Vaccine. 2004;23:321–324
   • View In Article
   • MEDLINE
   • CrossRef
5. Gerichter CH, Borusch D, Silberstein W. Some biological and technical aspects of smallpox vaccination. Jerusalem, Israel: Public Health Services, Israeli Ministry of Health; 1966;p. 30–35
   • View In Article
6. Frey SE, Newman FK, Yan L, Belsche RB. Response to smallpox vaccine in persons immunized in the distant past. JAMA. 2003;289:3295–3299
   • View In Article
   • CrossRef
7. Grabenstein JD, Winkenwerder W. US military smallpox vaccination program experience. JAMA. 2003;289:3278–3282
   • View In Article
   • CrossRef
8. Balicer R, Davidovitch N, Huerta M, Cohen D, Grotto I. Smallpox vaccination techniques: considerations and unresolved issues. Harefuah. 2005;144:51–5669
   • View In Article
   • MEDLINE
9. Balicer R, Grotto I, Huerta M, Leventhal A, Zach R, Yahalom V, et al. Beveled needle technique is not associated with low ‘take’ rates in Israeli smallpox revaccination campaign. Human Vaccines. 2005;1:224–227
   • View In Article
   • MEDLINE
   • CrossRef
10. Frey SE, Couch RB, Tacket CO, Treanor JJ, Wolff M, Newman FK, et al. Clinical responses to undiluted and diluted smallpox vaccine. N Engl J Med. 2002;346:1265–1274
    • View In Article
    • CrossRef
11. Couch RB, Winokur P, Edwards KM, Black S, Atmar RL, Stapleton JT, et al. Reducing the dose of smallpox vaccine reduces vaccine-associated morbidity without reducing vaccination success rates or immune responses. J Infect Dis. 2007;195:826–832
    • View In Article
    • MEDLINE
    • CrossRef
12. Nishiura H, Schwehm M, Eichner M. Still protected against smallpox? Estimation of the duration of vaccine-induced immunity against smallpox. Epidemiology. 2006;17:576–581
    • View In Article
    • MEDLINE
    • CrossRef
13. Nishiura H, Eichner M. Estimation of the duration of vaccine induced residual protection against severe and fatal smallpox based on secondary vaccination failure. Infection. 2006;34:241–246
    • View In Article
    • MEDLINE
    • CrossRef
14. Orr N, Forman M, Marcus H, Lustig S, Paran N, Grotto I, et al. Clinical and immune responses after revaccination of Israeli adults with the Lister strain of vaccinia virus. J Infect Dis. 2004;190:1295–1302
    • View In Article
    • MEDLINE
    • CrossRef