# Presentation: 390586

## Smallpox and Smallpox Vaccine

**Epidemiology and Prevention of Vaccine-Preventable Diseases**
**National Immunization Program**
**Centers for Disease Control and Prevention**

**Revised January 2006**

## Note: additional smallpox-related material, including images, slide sets, rash illness algorithm posters and worksheets, and videotapes are available on the CDC smallpox website at

**http://www.emergency.cdc.gov/agent/smallpox/**

## Smallpox

**First described in Chinese text in 4****th**** century**
**Vaccine developed in late 18****th**** century**
**Last case in U.S. in 1949**
**Last indigenous case on earth ****in 1977**

## Variola Virus

***Orthopoxvirus***
**Infects only humans in nature**
**May remain viable in crusts for years at room temperature**
**Rapidly inactivated by UV light, chemical disinfectants**

**Notes:**
Other orthopoxviruses that infect humans are vaccinia, cowpox and monkeypox.
Culture needed to differentiate variola from other orthopoxviruses.
Rapidly inactivated by bleach and Lysol.
No evidence strains with different virulence.  Severe disease a result of host factors.

## Smallpox Pathogenesis

**Virus contact with oropharyngeal or respiratory mucosa**
**Virus replication in regional lymph nodes**
**Viremia on about 8****th**** day of infection**
**Virus replication in oral and pharyngeal mucosa and skin**

## Variola major
 severe illness
 case-fatality rate of >30%
Variola minor
 less severe
 case-fatality rate of <1%

** ****severe illness**
** ****case-fatality rate of **_**>**_**30%**
**Variola minor**
** ****less severe**
** ****case-fatality rate of **_**<**_**1%**

- Smallpox Clinical Presentations

**Notes:**
Variola major the only type known until end of 19th century. Occurred in Asia and parts of Africa. Last case in Bangladesh in 1975.
Variola minor first described in South Africa in 1904. Predominant type in Americas and 20th century Africa.  Last case in Somalia in 1977.

## Clinical Presentations of Variola Major

**Ordinary (**_**>**_**90% of cases in unvaccinated persons)**
**Modified (mild; occurs in previously vaccinated persons)**
**Flat (uncommon; usually fatal)**
**Hemorrhagic (uncommon; usually fatal)**

**Notes:**
Types based on nature and evolution of skin lesions.  The relative vigor of the immune response probably determined clinical presentation.  On evidence of different strain of virus causing different presentations.

## Smallpox Prodrome

**Incubation period 12 days (range 7-17 days)**
**Prodrome**
**abrupt onset of fever **_**>**_**101****°****F**
**malaise, headache, muscle pain, nausea, vomiting, backache**
**lasts 2-4 days**
**not infectious until lesions develop in mouth**

## Smallpox Rash

**Enanthem (mucous membrane lesions) appears approx. 24 hours before skin rash**
**Minute red spots on the tongue and oral/pharyngeal mucosa**
**Lesions enlarge and ulcerate quickly**
**Virus titers in saliva highest during first week of illness**

## Smallpox Rash

**Exanthem (skin rash) appears ****2-4 days after onset of fever**
**First appears as macules, usually on the face**
**Lesions appear on proximal extremities, spread to distal extremities and trunk**

## Smallpox Rash Evolution

_**Stage**_
**Macules**
**Papules**
**Vesicles**
**Pustules**
**Crusts**
**All crusts****separated**

**Days after**_**Rash Onset**_
**0-1**
**2-3**
**3-5**
**6-12**
**13-20**
**21-28**

## Smallpox Rash

**Vesicles often have a central depression (“umbilication”)**
**Pustules raised, round, firm to the touch, deeply embedded in the skin**
**Lesions in any one part of the body are in same stage of development**
**Most dense on face and distal extremities (centrifugal distribution)**
**Lesions on palms and soles (**_**>**_**50% of cases)**

## Occurs in previously vaccinated persons
Prodrome may be less severe
No fever during evolution of rash
Skin lesions evolve more quickly
Rarely fatal
More easily confused with chickenpox

**Prodrome may be less severe**
**No fever during evolution of rash**
**Skin lesions evolve more quickly**
**Rarely fatal**
**More easily confused with chickenpox**

- Modified Smallpox

## Flat Smallpox

**Severe prodrome**
**Fever remains elevated throughout course of illness**
**Extensive enanthem**
**Skin lesions soft and flat, contain little fluid**
**Most cases fatal**

## Hemorrhagic Smallpox

**Prolonged severe prodrome**
**Fever remains elevated throughout course of illness**
**Early or late hemorrhagic signs**
**Bleeding into skin, mucous membranes, GI tract**
**Usually fatal**

## Bacterial infection of skin lesions
Arthritis
Respiratory
Encephalitis
Death
30% overall for ordinary smallpox
40%-50% for children <1 year
>90% for flat and hemorrhagic smallpox

**Arthritis**
**Respiratory**
**Encephalitis**
**Death**
**30% overall for ordinary smallpox**
**40%-50% for children <1 year**
_**>**_**90% for flat and hemorrhagic smallpox**

- Smallpox Complications

## The most important differentiating feature between smallpox and other rash illnesses is the presence of fever before rash onset

- Differential Diagnosis

## Differential Diagnosis

**Severe, febrile prodrome**
**1-4 days before rash**
_**>**_**101****o****F**
**Other symptoms:**
**prostration**
**headache**
**backache**
**chills**
**abdominal pain**
**vomiting**

**Mild or no prodrome**
**Little or no fever**
**No associated symptoms**

_**Smallpox**_

_**Varicella**_

## Deep, hard lesions
Round, well circumscribed
Confluent or umbilicated
Lesions at same stage of development

**Round, well circumscribed**
**Confluent or umbilicated**
**Lesions at same stage of development**

**Superficial lesions**
**Not well circumscribed**
**Confluence and umbilication not common**
**Lesions at all stages of development**

_**Smallpox**_

_**Varicella**_

- Differential Diagnosis

## Common Conditions With Vesicular or Pustular Rashes

**Varicella (primary infection with VZV)**
**Disseminated herpes zoster**
**Impetigo**
**Drug eruptions and contact dermatitis**
**Erythema multiforme minor**
**Erythema multiforme incl. Stevens Johnson syndrome**
**Enteroviruses incl. Hand, Foot and Mouth disease**
**Disseminated herpes simplex**
**Scabies and insect bites**
**Molluscum contagiosum**

## Smallpox Major Criteria

**Febrile prodrome 1-4 days before rash onset; fever of **_**>**_**101****°****F, and at least 1 additional symptom***
**Rash lesions are deep, firm/hard, round and well circumscribed**
**On any one part of the body lesions in same stage of development**

***Prostration, headache, backache, chills, vomiting**
**  ****or severe abdominal pain**

## Smallpox Minor Criteria

**Greatest concentration of lesions on face and distal extremities**
**Lesions first appear on oral mucosa/palate, face, or forearms**
**Patient appears toxic or moribund**
**Lesions evolve from macules to papules to pustules **
**Lesions on palms and soles**

## Risk of Smallpox by Clinical History and Examination

**High risk**
** ****febrile prodrome**
** ****classic smallpox lesions**
** ****same stage of development**
**Moderate risk**
** ****febrile prodrome**
** ****1 major OR **_**>**_**4 minor criteria**
**Low risk**
**no febrile prodrome**
**febrile prodrome and <4 minor criteria**

## Laboratory Confirmation

**Rapid diagnostic testing for varicella zoster virus (DFA, IFA, PCR)**
**Electron microscopy (may identify *****Orthopoxvirus***** but not specific for variola)**
**Culture**
**Nucleic acid-based testing**
**Serologic testing**

**Notes:**
Most important lab test is rapid testing for VZV such as direct flourescent antibody (DFA).  Electron microscopy and PCR may also be useful.
All laboratory testing for variola must be done at CDC.  Details of specimen collection and transport in Response Plan.

## Smallpox Medical Management

**Notify public health authorities **_**immediately**_** for suspected case**
**Strict respiratory and contact isolation**
**Supportive care**
**Antiviral agents?**

**Notes:**
Currently no specific medical treatment for smallpox other than supportive care.  Cidofovir may be effective but is not approved for use in smallpox; would require IND for use.  
Isolate to prevent transmission
Identify and vaccinate contacts, watch for symptoms of illness

## Smallpox Epidemiology

**Reservoir****	****	****  Human (before eradication)**
**Transmission****	****  Respiratory by large particles****	****	****	****	****  Can be airborne**** **
**Communicability****	****  From onset of rash until****	****	****	****	****  all crusts separate**

## Smallpox Epidemiology

**Most transmission results from face-to-face contact with infected person (household and  hospital contacts)**
**Transmission most frequent during first week of rash**

## Smallpox Eradication

**Intensified Global Eradication program begun in 1966**
**Initial strategy was mass vaccination**
**Strategy evolved to “surveillance and containment”**
**Last indigenous case in Somalia in October 1977**

## Smallpox Vaccine

- 1805	**	****	****Use of cows to produce vaccine**
- 1940s	**	****Freeze-drying technology**
- 1965	**	****	****Licensure of bifurcated needle**
- 1972	**	****	****Routine vaccination stopped in U.S.****	**
- 1983**	****	****	****Vaccine removed from civilian market**

## Smallpox Vaccine

**Live vaccinia virus in calf lymph**
**Contains trace amounts of polymyxin B, streptomycin, tetracycline, and neomycin**
**Diluent contains glycerin and phenol**
**New vaccine produced using cell culture technology does not contain antibiotics**

**Notes:**
Original diluent contains 50% glycerin, 0.25% phenol in sterile water for injection, 0.005% brilliant green.  0.25 ml of diluent yields about 100 doses. New diluent does not contain brilliant green.

## Response to Smallpox Vaccination 

**Neutralizing antibody develops**
** ****10 days after primary vaccination**
** ****7 days after revaccination**
**>95% of primary vaccinees develop detectable neutralizing antibody**
**Antibody persists >10 years**

## Smallpox Vaccine Efficacy

**Clinical efficacy estimated in household contact studies**
**91%-97% reduction in cases among contacts with vaccination scar**
**Studies did not consider time since vaccination or potency of vaccine**

## Duration of Immunity Following Smallpox Vaccination

**High level of protection (~100%) for up to 5 years following vaccination**
**Substantial but waning immunity for **_**>**_**10 years**
**Reduction in disease severity among previously vaccinated persons**

## Smallpox Fatality Rate by Time Since Vaccination—Europe, 1950-1971*

***Mack TM.  *****J Infect Dis***** 1972;125:161-9.**

## Postexposure Vaccine Efficacy

**Secondary attack rates reduced up to 91% compared to unvaccinated contacts**
**Lowest disease rates among persons vaccinated <7 days after exposure**
**Disease generally less severe (modified-type) in persons receiving postexposure vaccination**

## Post Exposure Vaccine Efficacy

**Postexp vacc**
**Never vacc**
**Vacc **_**<**_**10 days**
**Never vacc**
**Vacc **_**<**_**7 days**
**Never vacc**

_**% with smallpox**_
**29.5**
**47.6**
**75.0**
**96.3**
**1.9**
**21.8**

**Madras**
**Pakistan**
**Pakistan**

## Clinical Response to Smallpox Vaccination* 

_**Symptom/Sign**_
**Papule**
**Vesicle**
**Pustule**
**Maximum erythema**
**Scab**
**Scab separation**

_**Time after vac**_
**3-4 days**
**5-6 days**
**7-11 days**
**8-12 days**
**14 days**
**21 days**

***typical response in a nonimmune person**

## Clinical Response to Smallpox Vaccination 

**Major (primary) reaction**
**indicates viral replication has occurred and vaccination was successful**
**considered to be protected with the development of a major reaction**
**Equivocal reaction**
**indicates immune suppression of viral replication, allergic reaction without production of immunity, incorrect vaccination technique, or impotent vaccine**
**revaccinate immediately**

## Evolution of U.S. Smallpox Vaccine Recommendations

- 1972**	****Discontinue routine vaccination**
- 1976**	****Discontinue vaccination of HCWs**
- 1980**	****Vaccine recommended for lab****	****	****workers**
- 1990**	****Discontinue vaccination of military**
- 1991**	****Consider vaccine for HCWs****	****	****exposed to recombinant vaccinia**
- 2001**	****Bioterrorism guidelines**
- 2002**	****Smallpox Response Teams**

## Smallpox VaccineIndications in Nonemergency Situations

**Laboratory workers who handle cultures or animals infected with non-highly attenuated vaccinia**
**Laboratory workers exposed to other Orthopoxviruses that infect humans**
**Consider for other healthcare workers with contact with contaminated material**
**Public health, hospital, and other personnel who may need to respond to a smallpox case or outbreak**
**Persons who vaccinate others**

## Smallpox VaccineIndications in Emergency Situations*

**Persons exposed to initial release**
**Close contact with confirmed or suspected case**
**Direct care or transportation of confirmed or suspected case-patient**
**Laboratory personnel**
**Persons with risk of contact with infectious materials from patient**
**Other groups as recommended by public health authorities**

***following confirmation of a case of smallpox**

## Smallpox Vaccine

**Schedule**
**1 successful dose**
**Revaccination**
**10 years (non-highly attenuated vaccinia and recombinants)**
**3 years (more virulent Orthopoxviruses)**

## Smallpox Vaccine Local Reactions Among Susceptible Adults

**Pain, swelling, erythema at vaccination site**
**Regional lymphadenopathy**
**begins 3-10 days after vaccination**
**can persist for 2-4 weeks after vaccination site heals**

**Notes:**
Most primary vaccinees or distant re-vaccinees can expect some amount of tenderness, swelling, and redness at the vaccination site. They can also expect to have swollen axillary lymph nodes that can sometimes persist for several weeks.

## Smallpox Vaccine Reactions Among Susceptible Adults

**Elevated temperature**
**5%–9%  **_**>**_**100****°****F**
**3%         **_**>**_**102****°****F**
**Systemic symptoms (malaise, myalgia)**
**36% sufficiently ill to miss work, school, or recreational activities or had trouble sleeping**

**Notes:**
Fever most often occurs in people being vaccinated for the first time, and can be greater than 100 degrees Fahrenheit in more than 18% of vaccine recipients. Peak temperature elevation generally occurs about the time the vaccine site inflammatory reaction is at its greatest, on about days 8-10. General malaise and muscle aches may also occur and may be severe enough in some people to alter their normal activities for a couple of days.

## Smallpox Vaccine Adverse Reaction Rates*

| 
Reaction | Primary Vaccination |
| --- | --- |
| Inadvertent inoculation | 25-529 |
| Generalized vaccinia | 23-242 |
| Eczema vaccinatum | 10-39 |
| Progressive vaccinia | 0.9-1.5 |
| Postvaccinial encephalitis | 3-12 |
| Death | 1 |

***Rates per million primary vaccinations**

**Notes:**
This table shows the range of adverse event rates reported from both of these studies. The differences seen in the rates between the two studies is due to different data collection methods. The 10 state survey probably more accurately reflects the rates for frequently unreported less serious complications, while the national study captured the rates of the more serious adverse events through national reporting and VIG distribution mechanisms.

## Inadvertent Inoculation

**Caused by transfer of vaccinia virus from site of vaccination to other areas of the body**
**Most commonly on face, eyelid, nose, mouth, rectum, genitalia**
**Most lesions heal spontaneously without specific treatment**

## Generalized Vaccinia

**Results from viremia with implantations in the skin**
**Occurs in the absence of ****eczema or other preexisting ****skin diseases**
**Vesicles or pustules on normal skin distant from vaccination site**
**Usually minor illness with little residual damage**

## Eczema Vaccinatum

**Generalized spread of vaccinia on skin of patients with eczema or atopic dermatitis, or past history of eczema or atopic dermatitis**
**Occurs in vaccinees and contacts**
**Can occur whether eczema is active or quiescent**
**May be severe or fatal**

## Progressive Vaccinia

**Progressive necrosis at site of vaccination, often with metastatic lesions**
**Occurs in patients with impaired immunologic function, particularly cellular immunodeficiency**
**Frequently fatal**

## Postvaccinal Encephalitis

**Highest risk among children ****<12 months of age and older persons receiving primary vaccination**
**Believed to result from autoimmune or allergic reaction**
**Frequently fatal or neurologic sequelae**

## Fetal Vaccinia

**<50 fetal vaccinia cases reported in world literature**
**Most result from primary vaccination of mother early in pregnancy**
**Usually results in stillbirth or death of infant soon after delivery**
**Congenital malformations not reported**

## Smallpox VaccineContraindications and Precautions(Nonemergency Situations)

**Severe allergic reaction to a vaccine component or following a prior dose**
**Immunosuppression in the recipient or household contact**
**Physician-diagnosed heart disease or risk factors for heart disease**
**Pregnancy in the recipient or household contact**
**Breastfeeding**

## Smallpox VaccineContraindications and Precautions(Nonemergency Situations)

**Eczema or atopic dermatitis (current or past history) in the recipient or household contact**
**Acute, chronic, or exfoliative skin conditions (until improved or resolved) in the recipient or household contact**
**Children <12 months of age**
**Moderate or severe acute illness**

## Smallpox VaccineContraindications and PrecautionsEmergency (Postrelease) Situations

**Exposed persons—no contraindications**
**Unexposed persons—same as nonemergency situations**

## Vaccinia Immune Globulin Intravenous

**Immunoglobulin fraction of plasma from persons vaccinated with vaccinia vaccine**
**Effective for treatment of eczema vaccinatum, progressive vaccinia, severe generalized vaccinia, and ocular vaccinia**
**Not effective in postvaccinial encephalitis**

**Notes:**
CDC is only source for VIG.  All VIG is under IND Protocol.

## Vaccine Storage and Handling

**Stable indefinitely at -4****°****F (-20****°****C)**
**Store unreconstituted vaccine at 35-46****°****F (2****°****-8****°****C)**
**Reconstituted vaccine must be used within 90 days**
**Avoid contamination after opening vial**

## Smallpox Response Plan

**Key elements:**
**surveillance and investigation of cases**
**contact tracing**
**isolation guidelines**
**specimen collection and handling**
**communications**
**decontamination**

## Smallpox Response Teams

**Emergency, healthcare workers and other critical personnel may be asked to volunteer to receive the vaccine**
**Department of Defense will also vaccinate certain personnel who are or may be deployed in high threat areas**
**Some personnel assigned to certain overseas embassies may be offered vaccination**
**Does not include a recommendation for vaccination of the general public**

## Bioterrorism Information

**CDC Emergency Preparedness and Response Website**
**www.emergency.cdc.gov**

## National Immunization ProgramContact Information

**Telephone****	****	****800.CDC.INFO**** **
**Email****	****	****	****nipinfo@cdc.gov**** **
**Website****	****	****www.cdc.gov/vaccines**