Adverse Reactions after Smallpox Vaccination and Adverse Reaction Treatment by Vaccinia Immune Globulin

Abstract

The smallpox vaccine, which is based on vaccinia virus, has been effective in preventing this disease. Since the World Health Organization declared the eradication of smallpox in 1980, there has been no concern about the natural occurrence of smallpox, so vaccinations of the general population is not currently being conducted. However, as the variola virus is a pathogen that is possibly to be used in bioterrorism and is vaccinated against bioterrorism response personnel and people who may be exposed to the virus. These smallpox vaccines can cause local and minor adverse reactions, and in the case of the first and second generation smallpox vaccines, serious life-threatening complications may occur. Accordingly, vaccinia immune globulin (VIG) is used as a treatment for abnormal reactions caused by vaccination of the smallpox. However, since “VIG” is produced using the sera of people vaccinated against smallpox, the effectiveness and production between lots are variable, and demand may exceed supply. To compensate for these shortcomings, research and development of a smallpox vaccine side effect treatment that can be produced in various ways, based on human monoclonal antibodies with neutrality against the vaccinia virus and with standard effectiveness is underway.

Key messages

① What is known previously?

After the eradication of smallpox, general population vaccination against this disease was stopped.

② What new information is presented?

The smallpox vaccine can cause serious life-threatening adverse reactions as well as local and minor adverse reactions. Accordingly, VIG was used as a smallpox vaccine adverse reactions treatments.

③ What are implications?

Variola virus is a pathogen that can be abused for bioterrorism and is vaccinated bioterrorism response personnel and others. Accordingly, VIG, which used as a smallpox vaccine adverse reactions treatments, has a limit in production. To compensate for these shortcomings, the development of mass-produced and standardized neutralizing antibodies is underway, and it is necessary to introduce them.

Introduction

The variola virus belongs to the genus Orthopoxvirus in the family Poxviridae. It is the causative agent of smallpox, a once widespread and deadly disease. In the late 1700s, Edward Jenner developed the cowpox-based vaccination method, the basis of the smallpox vaccine, after discovering that cattle farmers who had previously experienced mild cowpox symptoms had a lower smallpox incidence than the general population [1,2]. Following the introduction of the global smallpox vaccination program by the World Health Organization (WHO) in 1967, naturally occurring smallpox infections have been successfully eradicated [3]. In 1980, after WHO announced the successful eradication of smallpox, vaccinia virus vaccination began to be phased out. Given the high potential of the variola virus to be used as a bioterrorism agent, many countries continue to vaccinate individuals at risk of exposure, such as bioterrorism response personnel, healthcare professionals, and laboratory staff [4]. The Republic of Korea (ROK) stockpiled second-generation smallpox vaccines and provides them to bioterrorism response personnel to prepare for public health emergencies. Most approved vaccinia virus-based smallpox vaccines are attenuated live vaccines that prevent orthopoxvirus infections. Smallpox vaccines have local and mild adverse reactions, while first and second-generation smallpox vaccines may even cause life-threatening complications. Thus, vaccinia immune globulin (VIG) is used to treat adverse reactions to smallpox vaccination [5]. This study describes smallpox vaccination adverse reactions and introduces VIG as a therapeutic agent for these adverse reactions.

Adverse Reactions to Smallpox Vaccination

Smallpox vaccines are live vaccines containing the vaccinia virus. While they effectively prevent smallpox, introducing the living vaccinia virus in the injection site may induce several adverse reactions. In particular, first- and second-generation smallpox vaccines may cause serious adverse events, such as progressive vaccinia [5-9].

1. Local Reactions

A local reaction around the injection site is the most common smallpox vaccine adverse reaction. These local reactions generally occur within a few days after vaccination, including erythema, swelling, tenderness, itchiness, and pustules or vesicles. Pustules eventually become scabs and fall off, leaving a small scar.

2. Systemic Symptoms

In some cases, mild systemic symptoms may occur following vaccination. These symptoms include fever, fatigue, headache, muscle pain, and overall discomfort, and may occur within a week after vaccination. These symptoms are transient in most cases and resolve spontaneously.

3. Accidental Infection or Accidental Inoculation

Accidental inoculation is the most common adverse reaction. Accidental virus inoculation from the injection site to a body part that comes into close contact with the injection site might cause lesions. The face, eyelids, nose, mouth, genital area, and anus are the most affected body parts. Most lesions heal without any treatment.

4. Lymphadenopathy

Lymphadenopathy around the vaccination site is a common adverse reaction to smallpox vaccines. Lymph nodes may enlarge and tenderness may be felt in the lymph nodes as a result of the immune response caused by the vaccine. This is a normal physiological response and generally resolves spontaneously without complications.

5. Generalized Vaccinia

Generalized vaccinia causes systemic erythematous or pustular rash 6–9 days after vaccination. Patients with mild generalized vaccinia may recover without treatment. However, those with severe or recurrent conditions require VIG [10].

6. Eczema Vaccinatum

Eczema vaccinatum is rare but relatively more common among people with pre-existing atopic dermatitis or eczema. Localized or extensive pustular or papular rash may occur, most likely around areas previously affected by atopic dermatitis. The rash is often accompanied by fever and lymphadenopathy [10].

7. Progressive Vaccinia

Progressive vaccinia is an extremely rare but severe adverse reaction of smallpox vaccination affecting individuals with immunodeficiency. It typically affects immunocompromised patients, including those with HIV/AIDS or undergoing immunosuppressant therapy. Progressive vaccinia may hinder the healing of the vaccination site and lead to necrosis or occasionally metastasize to other areas of the body (skin, bones, and internal organs). VIG and antiviral agents have increased the survival rate of progressive vaccinia, which was previously fatal [10].

8. Postvaccinal Encephalitis

Postvaccinal encephalitis occurs in 2 to 1,200 people per million vaccinated people and 8–15 days after vaccination [5]. Sudden death can occur within a week of symptoms and the mortality rate is around 25%. Although the pathogenesis of postvaccinal encephalitis remains unclear, it is similar to that of postviral encephalitis in most cases. Its symptoms include fever, vomiting, headache, and discomfort. In some cases, it may lead to coma and meningitis.

The Discovery and Production of VIG

In the late 1940s, Henry Kempe proposed isolating gamma globulin antibodies from the serum of individuals who had received the smallpox vaccine and administering a purified version to individuals with or at risk for adverse reactions. Kempe observed that some infants did not react to the smallpox vaccination, possibly due to high maternal antibodies against the vaccinia virus, which inhibited the replication of the vaccinia virus in the smallpox vaccine. Additionally, he inferred that the localized skin pocks at the vaccination site that heal without spreading systemically and the development of immunity to smallpox were probably the result of the generation of antibodies against the vaccinia virus in response to vaccination, preventing the virus from replicating and spreading beyond the vaccination site. He observed that smallpox vaccination that failed to produce antibodies against the vaccinia virus caused severe adverse reactions such as generalized vaccinia or eczema vaccinatum. Based on these observations, Henry Kempe proposed that immune globulin from individuals with high level of antibodies against the vaccinia virus after smallpox vaccination could help those who had complex adverse reactions or were expected to have severe adverse reactions due to antibody production problems [11].

In the 1950s, gamma globulin was produced from the plasma of U.S. military personnel who were hyperimmune to the vaccinia virus following smallpox vaccination. It was used as a therapeutic agent to treat adverse reactions to the smallpox vaccine [12]. Intramuscular injections of gamma globulin were found to be effective in treating adverse reactions, such as generalized vaccinia and eczema vaccinatum, and repeated doses over several weeks were effective in treating progressive vaccinia [6,12]. Furthermore, it can be used as prophylaxis against adverse reactions to the smallpox vaccine. First- and second-generation smallpox vaccines are contraindicated for individuals with skin conditions such as atopic dermatitis, those with weakened immune systems such as those having HIV/AIDS, and specific populations including pregnant women. However, VIG could be administered prophylactically in these individuals before smallpox vaccination to prevent potential adverse reactions [5].

VIG is classified into two types based on the route of administration: vaccinia immune globulin intramuscular (VIGIM) and VIG intravenous (VIGIV). VIGIM is used to treat smallpox vaccine complications, while the key benefit of VIGIV is improved dosing and tolerability compared to VIGIM.

Viral contamination must be minimized during VIGIV production. VIGIV is purified via ion-exchange chromatography from plasma collected from healthy donors who received Dryvax^® (Wyeth-Ayerst Laboratories, lnc.; vaccinia virus live vaccine). The purified gamma globulin solution is then sterilized through solvent/detergent treatment and stabilized using 10% maltose and 0.03% polysorbate 80 (pH 5.0–6.5).

All plasma donated for VIGIV production undergoes U.S. Food and Drug Administration (FDA)-approved serological testing for the presence of antibodies to Hepatitis B surface antigen, HIV-1/2, and hepatitis C virus (HCV), along with nucleic acid testing for HBV, HIV-1, and HCV. The efficacy of VIGIV is determined through neutralizing antibody assays [5].

When VIGIV was administered to healthy individuals, adverse reactions, including headache and local reactions at the injection site, and nausea were reported in 5–7% of cases, with no cases of serious adverse events. Nevertheless, caution should be exercised for individuals with selective IgA deficiency, as VIGIV contains some IgA and may trigger an anaphylactic reaction [5,13].

Smallpox vaccination adverse reactions can be treated and prevented with VIG. The ROK stores it as a national essential medicine for bioterrorism and infectious disease epidemics after FDA certification in 2005. However, because it is made from the serum of individuals vaccinated with the smallpox vaccine, its efficacy and production volume fluctuate between lots, and supply may be insufficient. To address this drawback, research and development are underway to create therapeutic agents for smallpox vaccine adverse reactions that can be mass-produced and have standardized efficacy based on combinations of human monoclonal antibodies with neutralizing properties against the vaccinia virus. Viruses in the genus Orthopoxvirus, such as the vaccinia virus, consist of over 200 proteins and their encoding DNA. These viruses share high orthology in their genes and proteins. Experiments using mouse models have shown that antibodies against the H3 and B5 surface antigens of the vaccinia virus play a critical role in neutralizing infections caused by viruses within the genus Orthopoxvirus and that these antibodies have equivalent efficacy to that of VIG [14]. Furthermore, experiments involving the production and combination of monoclonal antibodies targeting the major antigens (A27, D8, H3, L1, B5, and A33) of the vaccinia virus demonstrated equivalent or superior cellular infection neutralization and defense against animal infections caused by viruses within the genus Orthopoxvirus compared to VIG [14,15].

Conclusion

The smallpox vaccine is a live vaccine that contains the vaccinia virus and is generally effective in preventing smallpox. The vaccine can cause mild and localized adverse reactions, while first and second-generation vaccines can induce more severe adverse reactions. The most common adverse reactions include erythema, swelling, tenderness, and itching around the injection site. However, life-threatening conditions may develop in immunocompromised individuals.

The discovery of VIG in the late 1940s offered a cure for severe adverse reactions associated with smallpox vaccine immunization. It was speculated that obtaining VIG from individuals who developed antibodies and immunity against the vaccinia virus after smallpox vaccination and transfusing it to people who developed adverse reactions or were expected to develop them due to their immunocompromised state would help treat and prevent them. In the late 1950s, gamma globulin was produced from the plasma of U.S. military personnel who were hyperimmune to the vaccinia virus following smallpox vaccination and used to treat adverse reactions to the smallpox vaccine.

Smallpox vaccination helped eradication of the deadly smallpox infection in human population. General smallpox immunization has been discontinued because spontaneous smallpox infections have not occurred since eradication. Bioterrorism response personnel and laboratory staff receive smallpox vaccinations since the virus could be exploited in bioterror attacks. Smallpox vaccination is no longer routinely administered for infection prevention because of the local and mild adverse reactions following vaccination and the potential adverse reactions to first- and second-generation vaccines. The ROK recently introduced safe third-generation smallpox vaccines that do not replicate in the body. However, they are only administered to high-risk populations in response to the potential monkeypox outbreak.

VIG, which is mainly used to treat adverse reactions to the smallpox vaccine, is produced from the plasma of smallpox-vaccinated individuals. Therefore, its efficacy varies and production is limited, which may lead to inadequate supply. Research is underway to develop mass-produced therapeutic agents based on a combination of monoclonal antibodies with vaccina virus neutralizing abilities.