Smallpox Vaccine: Overview for Health Care Response Teams Thomas G. Franck, MD, MPH Regional Physician Consultant Office of Emergency Preparedness & Response Virginia Department of Health January 2003

Objectives To briefly review smallpox disease To gain an in depth understanding of smallpox vaccine, including: history of smallpox vaccination overview of vaccinia indications contraindications normal response complications 1.To briefly review smallpox disease; 2.To provide an in depth review of smallpox vaccine, including: brief history of smallpox vaccination overview of vaccinia vaccinia vaccine indications and contraindications normal response to vaccinia vaccination adverse events from vaccinia vaccination

Taxonomy Family: Poxviridae Genus: Orthopoxviruses Smallpox (variola) Cowpox Monkeypox Vaccinia Although there are several other members of the genus of viruses called orthopoxviruses, the four listed here represent those that can infect humans. These four viruses have about 93% of their DNA in common, which accounts for their cross-reactivity and the ability to employ one as a vaccination that protects against the others. 93% DNA Homology

Smallpox Caused by Variola virus Unique to humans Person-to-person spread usually via close contact - droplets contaminated materials (uncommon) aerosolized droplet nuclei spread (rare) 30% case-fatality rate on average Let’s begin by reviewing some major aspects of smallpox disease. Here is an electron micrograph of variola major virus. It’s a large, enveloped, brick-shaped DNA virus belonging to the family Poxviridae and the genus of Orthopoxviruses.

Smallpox: Clinical Features Incubation: 12-14 days (range 7-17) Prodrome: lasts 2-4 days fever, malaise, headache, backache, vomiting Eruptive stage (Rash): Oral cavity/pharynx  face, hands, forearms  lower extremities  trunk Synchronous progression: maculopapules  vesicles  pustules  scabs Lesions on palms /soles Infectious stage (especially 1st week) Smallpox disease can be divided into 3 phases: the incubation period, the prodrome, and the eruptive stage.

This series of photographs demonstrates the typical progression and distribution of smallpox rash.

Here is a fairly classic presentation of a child with smallpox. This is smallpox due to variola major, ordinary type, which is the most common form.

Smallpox - Treatment Treatment Prevention/Prophylaxis Supportive care No treatment proven effective Experimental treatment with antivirals, e.g., Cidofovir Prevention/Prophylaxis Vaccination - protective if given within 3 days of exposure

Smallpox: Why the Concern Now? Last case in US in 1949 Last naturally acquired case in 1977 Disease declared eliminated by WHO in 1980 Stocks of Variola virus held by U.S. & Russia Bio Weapons programs in several countries Recent Intelligence review: 4 countries may have covert stocks of smallpox virus – Russia, Iraq, North Korea, and France

Smallpox Vaccine: History 1796: Edward Jenner develops vaccine (cowpox) 1805: Use of cows to produce vaccine 1940s: Freeze-drying of Vaccinia 1965: Licensure of bifurcated needle 1972: Routine vaccination stopped in U.S. 1983: Vaccine removed from civilian market 1990: U.S. Military vaccination stops

Edward Jenner (1749–l823) the “father” of vaccination. In the background is a dairymaid (or milkmaid) working with some cows. (Courtesy of the Institute of the History of Medicine, The Johns Hopkins University, Baltimore, MD.)

Jenner transferred “matter” from the hand of an infected dairymaid to 8 year-old James Phipps on 14 May 1796. It turns out this matter was cowpox virus. Jenner demonstrated that a person inoculated and infected with cowpox was protected against smallpox. The procedure, which he called vaccination, represented the first use of a vaccine in the prevention of disease.

English engraving by James Gillray, 1802 Here we see Jenner vaccinating someone with cowpox. It’s an excellent capture of the anxiety felt by the population at the time, similar to what some of us may be experiencing today.

Compare the results of variolation with vaccination. (Captain C. Gold, 1801, Courtesy of the Library, London, Wellcome Institute for the History of Medicine.)

Smallpox Vaccine Live virus called “Vaccinia” An orthopoxvirus, genetically distinct from other orthopoxviruses such as cowpox, monkeypox, and variola (cause of smallpox) Origin unknown: May be a virus now extinct in nature

Vaccinia Vaccine “Dryvax” (Wyeth Laboratories) Contains NY City Board of Health strain 2.7 million doses licensed (phase 1)* Enough vaccine “to vaccinate every single person in the country in an emergency”* *December 2002

Vaccine Efficacy: Pre-Exposure Reduces chance of getting infected (i.e., decreases secondary attack rate) 91%-97% reduction in cases among case contacts with vaccination scar For those infected, reduces fatality rate and severity of disease How well does the vaccine protect someone if it is given prior to any exposure to smallpox?

Just to review: The case-fatality rate tells you this: once I am infected and become a case, what are my chances of dying. You can see from the graph that if you have been vaccinated, then you are relatively well-protected compared to those never having been vaccinated. And you are especially well-protected if vaccinated within the last 10 years. Mack, J. Inf Dis, 1972

Vaccine Efficacy: Post Exposure Generally prevents smallpox, or significantly decreases severity, if given within 3 days of exposure Vaccination 4 to 7 days post-exposure still offered protection to many people, but significantly less than vaccination before 4 days We have just seen that smallpox vaccination protects us when given in advance, prior to an exposure. But it can also be very effective even after you are directly exposed to smallpox, if given early enough. When estimates for prevention and disease modification are combined, fewer than 5% of all persons vaccinated within 3 days after exposure would be at risk for disease of normal severity

Vaccine Efficacy: Post Exposure Smallpox AR % 29.5 47.6 75.0 96.3 1.9 21.8 (Madras) (Pakistan) Postexp vacc Never vacc Vacc <10 days Vacc <7 days Another way to look at post-exposure vaccination efficacy is to examine secondary attack rates. In these 3 studies, the secondary attack rates varied considerably. What these studies demonstrate is that the risk of developing smallpox depended on whether or not you received any vaccination post-exposure. What is not quite so evident from these studies is the important finding that how quickly you received the vaccine after exposure to smallpox is critical to predicting your chances of survival.

Duration of Immunity High level of protection (95-100%) for 3-5 years following vaccination Immunity wanes after 5 years, but some residual protection evident at 10 and even 20+ years Reduction in disease severity with any history of vaccination However, best protection if vaccinated <3-5 yrs ago; we cannot rely on previous vaccinations to protect our population and we should consider the population to lack immunity to smallpox.

Smallpox Vaccine Indications: Non-Emergency Current Indications: Laboratory workers who handle cultures or animals infected with non-highly attenuated vaccinia or other Orthopoxviruses New Recommendations: Public health, hospital, and other personnel, generally 18-65 years of age, who may have to respond to a smallpox case or outbreak

Smallpox Vaccine Indications: Emergency Situations Ring Vaccination Persons exposed to initial release Close contact with confirmed or suspected case Direct care or transportation of confirmed or suspected case Laboratory personnel Persons with risk of contact with infectious materials from case Mass Vaccination of entire populations? There are basically 2 major strategies at our disposal when it comes to managing a smallpox outbreak. Some advocate ring vaccination and others advocate mass vaccination. Ultimately, it may depend on the nature of the smallpox outbreak.

Contraindications: Non-Emergency Situations Eczema/atopic dermatitis (active or history of) or household contact with eczema/atopic dermatitis Other active skin conditions (allergic rash, burns, impetigo, chickenpox, shingles, herpes,psoriasis, severe acne, etc.) or household contact with acitve skin condition Immunosuppression or household contact with immunosuppression Pregnancy or pregnant household contact Breastfeeding Infants (not advised in children < 18) Severe allergic reaction to prior vaccination or vaccine component

Contraindications: Immunodeficiency Conditions causing immunodeficiency: HIV, leukemia, lymphoma, other cancers, agammaglobulinemia, certain autoimmune disorders (e.g., SLE), other immune disorders Treatments causing immunodeficiency: Chemotherapy, radiation treatment, antimetabolites, alkyltating agents, organ transplant meds, high-dose corticosteroids Immunomodulatory medications? Unknown According to CDC, cancer chemotherapy or radiation treatment, current or within the past 3 months, is a contraindication. High dose corticosteroids: Equivalent to 2 mgm/kg or greater of oral prednisone daily, or 20 mgm/day, particularly if given for longer than 14 days. For certain immunomodulatory therapies, e.g., DMARDs for Rheumatoid Arthritis, there currently are no specific recommendations. According to the American College of Rheumatology, it may be prudent to avoid vaccination of such patients for now until further information becomes available. For those potential vaccinees with questionable contraindications or possible contraindications, we recommend consultation with a specialist in the appropriate field.

Contraindications: Eczema/Atopic Dermatitis Eczema: a red, itchy rash that lasts at least two weeks and then comes and goes It is estimated that at least 15 million people in U.S. have atopic dermatitis These people are at risk of a serious complication, eczema vaccinatum Here is one definition of eczema, as defined by an experienced group of dermatologists on the American Academy of Dermatology’s Bioterrorism Taskforce.

Contraindications: Emergency Situations Exposed persons – no contraindications Unexposed persons – generally same as non-emergency situations w/ some modifications, depending on situation Example: if there were a smallpox outbreak in the U.S., the category of children 1-17 years old would probably be eliminated as a contraindication.

Vaccine Administration Surgical needle Vaccinostyle Rotary lancet Jet injector Bifurcated needle* *Only administration technique currently in use.

Vaccination Technique

Invented by Dr. Benjamin A Invented by Dr. Benjamin A. Rubin of Wyeth Laboratories, patented in July 1965. Developed in conjunction with Reading Textile Machine Company. Bifurcation holds exactly 1 mg of water, slightly more vaccine because of increased viscosity. WHO procured about 50 million bifurcated needles between 1967 and 1976. The 1970 price was about US$5 per 1000.

This photo demonstrates good vaccination technique.

Vaccination Site Care Remember – live vaccinia virus is present at site of vaccination until scab falls off on its own, usually 2-3 weeks. Dressing Health care setting: 3 layers of protection – gauze, semipermeable dressing, shirt Non-health care setting: 2 layers of protection – gauze & shirt Avoid salves and ointments Avoid touching/scratching site and picking scab

Post-Vaccination Follow-up Semipermeable dressing: change dressing at least every 3-5 days and as needed Gauze dressing secured by tape: change dressing every 1-3 days and as needed “Take” evaluation: 7 days after vaccination (+/- 1 day) If significant side effects or adverse event, follow-up with designated health care provider

Clinical Response to Vaccination* Sign/symptom Papule Vesicle Pustule Maximum erythema Scab Scab separation Time after Vacc 3 days 5-6 days 7-11 days 8-12 days 14 days 21 days *typical response in a nonimmune person

Clinical Response to Vaccination Major (primary) reaction Indicates viral replication has occurred and vaccination was successful No reaction or equivocal reaction No immunity and vaccination must be repeated

Let’s look at what the expected response to vaccination should be. Here we see the typical progression of vaccinia. On day 7 we see here a “major reaction”, also known as a “take”.

Major Reaction* (6-8 days after vaccination) Primary vaccination Vesicular or pustular lesion Area of definite palpable induration surrounding a central crust or ulcer Revaccination Less pronounced and more rapid progression Pustular lesion or induration surrounding a central crust or ulcer *WHO Expert Committee on Smallpox, 1964

Primary Revaccination Day 3

Primary Revaccination Day 7

Primary Revaccination Day 10

Revaccination Primary Day 14

Normal Variants: Satellite Lesions

Normal Variants: Cellulitis & Lymphangitis

Smallpox Vaccination: Normal Side Effects Fever: 10% of adults Localized soreness: 35-47% Headache/muscle aches: 40-50% Redness/swelling > 3 inches: 15% 1/3 may feel bad enough to miss work, school, activity, or have trouble sleeping In a recent study, about one-third of vaccinees felt sick enough to miss work, school, social activity, or have disturbed sleep. In recent clinical trials, only about 5-10% of vaccinees actually missed work.

Smallpox Vaccination: Adverse Events Contact transmission: spread vaccinia to others Inadvertent autoinoculation: spread to other sites on body Generalized vaccinia: spread throughout body Eczema vaccinatum: severe skin reaction Progressive vaccinia (vaccinia necrosum) Postvaccinial encephalitis Death

Accidental Inoculation Accidental auto-inoculation of cheek with vaccinia virus, approximately 5 days old. Primary take on arm, 10-12 days old. Photo courtesy of John M. Leedom, MD.

Accidental Inoculation

Generalized Vaccinia Generalized vaccinia in an apparently normal child. Recovered without sequelae. Photo courtesy of John M. Leedom, M.D.

Generalized Vaccinia

Eczema Vaccinatum This is a more severe complication. This child had a history of atopic dermatitis when he was vaccinated.

Eczema Vaccinatum Again, you can see how severe this reaction can be. In fact, it can be fatal. Do not receive smallpox vaccination if you have any history of atopic dermatitis or “eczema.”

Progressive Vaccinia One of the worst complications is progressive vaccinia, which almost always occurs in someone with immunosuppression, and often this is a defect in cell-mediated immunity.

Post-Vaccinial Encephalitis Autoimmune process No predictors of susceptibility Supportive care; no specific therapy Vaccinia Immune Globulin is not effective and is not recommended. 15-25% mortality; and 25% had permanent neurological sequelae Any patient with an evolving central nervous system disorder should not receive a vaccination.

Vaccinia Keratitis This is caused by Vaccinia virus being deposited onto cornea, which leads to corneal infection or ulceration and subsequent clouding. Treatment – VIG is contraindicated. Combination of a topical antiviral and interferon speeds healing. Vidarabine Trifluridine Acyclovir

Vaccine Adverse Events Complication # per million Household transmission 27 Accidental autoinoculation 25-530 Generalized vaccinia 23-242 Eczema vaccinatum 10-39 Progressive vaccinia 1-1.5 Encephalitis 3-12 Death 1-2 Looking at the worst case scenario, these rates translate to the following: For generalized vaccinia: 1 per 4,000 For eczema vaccinatum: 1 per 26,000 For post-vaccinial encephalitis: 1 per 83,000 For progressive vaccinia: 1 per 667,000 Death: 1 per 1 million primary vaccinations 1 per 4 million revaccinations

Postvaccinal Encephalitis Inadvertent Autoinoculation Complication Rates of Vaccination Rates (per million vaccinations) U.S., 1968 (ten state survey) Complication 108 1254 Total 2 12 Postvaccinal Encephalitis 3 1.5 Progressive Vaccinia 39 Eczema Vaccinatum 9 242 Generalized Vaccinia 42 529 Inadvertent Autoinoculation Revaccination Primary Vaccination Complication Primary Vaccination Revaccination Inadvertent Autoinoculation 529 42 Generalized Vaccinia 242 9 Eczema Vaccinatum 39 3 Progressive Vaccinia 1.5 3 Postvaccinal Encephalitis 12 2 Total 1254 108

VIG: Vaccinia Immune Globulin Indicated: Eczema vaccinatum Progressive vaccinia Generalized vaccinia (if severe or recurrent) Accidental implantation (ocular or extensive lesions) Not Recommended: Accidental implantation (mild instances) Generalized vaccinia (mild or limited - most instances) Erythema multiforme Encephalitis Contraindicated: Vaccinia keratitis VIG is the Immunoglobulin fraction of plasma from persons vaccinated with vaccinia vaccine.

Issues for Discussion HIV testing Pregnancy testing Vaccination site care – who, how often? Should healthcare provider continue to work? Liability & workers’ compensation HIV testing – do we recommend or simply offer the test? Pregnancy – do we test? Site care for vaccinated site Gauze +/- semi-permeable bandage? How often to change dressing? Who? Who assesses for a “take” at 7 days? Can healthcare provider continue to work? CDC says “yes”, Wyeth says “no” Options: furlough vs reassignment vs normal duty

“…it now becomes too manifest to admit of controversy, that the annihilation of the Small Pox, the most dreadful scourge of the human species, must be the final result of this practice.” -Edward Jenner, 1801