US implementation of large-scale smallpox vaccination plan has special implications for people with HIV

1 April 2003. Related: Basic science and immunology.

Gareth Hardy, HIV i-Base

The increased threat of biological warfare has led to a renewed smallpox vaccination plan in the USA, which could be echoed by other countries including Britain.

In December, the US President, George W Bush, announced plans to vaccinate 500,000 key workers against the disease and an intention that by mid-2003 10 million US citizens would be vaccinated. However, on Tuesday 3 December the UK Department of Health (DoH) announced that it had no plans to introduce a mass vaccination programme against the disease and that only 700 key health and military staff would be vaccinated who would form new ‘Regional Smallpox Response Groups’ in the event of an attack.

Nevertheless the DoH report Guidelines for Smallpox Response and Management in the Post-Eradication Era did state that this policy could change if public demand for protection from smallpox increased. Thus the UK government is on course to stockpile 60 million doses of the vaccine.

Smallpox is caused by the variola virus, which belongs to the poxviridae family. This virus is highly contagious, airborn and persistent and has mortality rates ranging up to 40%. Between 1966 and 1973 the World Health Organisation (WHO) carried out a vigorous global programme of smallpox vaccination, which has culminated in eradication of variola virus from the human population. There is no known animal reservoir of variola, thus complete global eradication is now assumed. The last naturally occurring outbre ak of smallpox was in Somalia in October, 1977. Since then two reference stocks of variola have been stored at the Centres for Disease Control and Prevention, (CDC) in Atlanta, Georgia, USA and at the Research Institute for Viral Preparations in Moscow, Russia.

Persons aged younger than 30 are not likely to have been vaccinated or to have any protective immunity to the virus. Protective immunity to variola in those older than 30, who will have received childhood vaccination, is likely to have waned over the elapsed three decades since vaccination. The lack of vaccination for smallpox over the last 30 years leaves a world population with gradually returning susceptibility to the virus and a consequent liability for massive epidemics of the disease. Modern day rapid transport coupled with physicians’ unfamiliarity with the disease may both facilitate reintroduction of smallpox into the global human population if a new source of the virus emerged. The use of smallpox in biological weapons cannot be ruled out and would have the potential for devastating effects.

On 23 September 2002, the CDC presented its plan for renewed smallpox vaccination of the US population. In Clinical Infectious Diseases John G Bartlett of Johns Hopkins University, Baltimore, reviews the important aspects of smallpox vaccination strategies that affect those living with HIV and their health care providers. These considerations are a serious concern as vaccination for smallpox and its subsequent eradication occurred before HIV became apparent.

The main concern raised is the high risk of disease occurring in immunocompromised individuals as a direct result of vaccination for smallpox. The smallpox vaccine is a live attenuated virus of the poxviridae family known as vaccinia virus, which is closely related to the variola virus. The vaccinia virus is derived from cowpox, or possibly horsepox. Due to successive propagation in many laboratories the vaccinating strain has become considerably attenuated and while it is very similar to variola virus, vaccinia itself rarely causes serious complications in healthy individuals.

There are several contra-indications for inoculation with vaccinia virus that apply to potential vaccinees and laboratory or healthcare workers whose work may involve handling the virus. These contra-indications include eczema and immunosuppression. Cell mediated immune responses play a major role in protection from There are several contra-indications for inoculation with vaccinia virus that apply to potential vaccinees and laboratory or healthcare workers whose work may involve handling the virus. These contra-indications include eczema and immunosuppression. Cell mediated immune responses play a major role in protection from vaccinia dissemination and disease in healthy individuals. In HIV-positive people the impairment of this component of the immune response removes protection from disease such that generalised or progressive vaccinia (vaccinia necrosum) may occur. This reaction to smallpox vaccination may affect anyone with compromised immune responses, including people with HIV, organ transplant recipients, patients undergoing cancer chemotherapy, patients receiving long-term cortico-steroid therapy, patients with haematologic malignancies, and patients with congenital immunodeficiencies. Vaccinia necrosum has also rarely been seen in patients with agammaglobulinaemia. Dissemination of cutaneous lesions from the primary site of inoculation occurs, with viraemic spread, involving minimal lymphocytic infiltration. This reaction may result from primary vaccination or from revaccination and is usually fatal. dissemination and disease in healthy individuals. In HIV-positive people the impairment of this component of the immune response removes protection from disease such that generalised or progressive vaccinia (vaccinia necrosum) may occur. This reaction to smallpox vaccination may affect anyone with compromised immune responses, including people with HIV, organ transplant recipients, patients undergoing cancer chemotherapy, patients receiving long-term cortico-steroid therapy, patients with haematologic malignancies, and patients with congenital immunodeficiencies. Vaccinia necrosum has also rarely been seen in patients with agammaglobulinaemia. Dissemination of cutaneous lesions from the primary site of inoculation occurs, with viraemic spread, involving minimal lymphocytic infiltration. This reaction may result from primary vaccination or from revaccination and is usually fatal.

Very limited experience of smallpox vaccination in persons with HIV enables some case studies and observational reports, which Bartlett discusses. These studies were made before the HAART era and the patients in them had AIDS. Smallpox vaccination is thus considered clearly unsafe in persons with CD4 counts <200 cells/ml blood. However an assumption of safety in HIV-positive persons with CD4 counts >200 cells/ml blood is problematic. Additionally the impact of HAART on susceptibility to vaccinia necrosum is unknown. The CDC recommendations state that HIV infection is a contra-indication for smallpox vaccination, regardless of CD4 count.

Since smallpox vaccination in people with HIV is unsafe, the risk to people with HIV from an outbreak of smallpox is enormous. While the smallpox mortality rate in unvaccinated immunocompetent subjects is up to 30 or 40%, the expected mortality rate in HIV-positive individuals is speculated to be much higher and to inversely correlate with CD4 count. In persons with AIDS the smallpox mortality rate would be expected to be very high.

For HIV-positive individuals older than 30 years, who received childhood vaccination for smallpox, remaining immunity is likely to be negligible. Even in HIV-negative persons antibodies to vaccinia are now largely undetectable and cell mediated responses are likely to be low. The smallpox vaccine is considered to confer protection for only three to seven years, although recent evidence suggests protection may last longer. The impact of HIV induced immunosuppression on this is unlikely to leave any protective immunity to smallpox.

Thus the CDC states that smallpox vaccination will be voluntary. In the event of an outbreak of infection, anyone who has been potentially exposed will be advised to receive smallpox vaccine, regardless of their medical condition. In immunocompetent individuals protective immunity develops seven to 10 days after vaccination, which can prevent disease developing if vaccination is administered quickly after exposure, given that the incubation period of smallpox is about 12 days. Hence smallpox is one of the few examples of the utility of post-exposure, therapeutic vaccination, as also is the case for rabies and tetanus. The CDC also recommends that before vaccination a medical screen should be performed, including HIV testing, with informed consent. The CDC states that in the presence of HIV infection, smallpox vaccination should not be recommended, unless there is a smallpox attack.

The problems posed to HIV-positive individuals from smallpox vaccination go beyond those of direct, voluntary vaccination. Other non-immunocompromised persons, vaccinated for smallpox, also present a significant risk for persons with HIV. Inoculation with vaccinia results in localised ulceration, which sheds virus for approximately 10-14 days subsequently. Shedding even occurs through sealed bandages. Thus there is a risk of secondary spread of vaccinia. The frequency of such cases is low at two to six cases per 100,000 primary vaccinations and requires close contact. The frequency of progressive vaccinia developing as a result of such secondary spread was very rare during the smallpox eradication programme. However there is concern that because of the increased number of immunodeficiencies now, such as HIV, the frequency of progressive vaccinia from secondary contact may be higher. Thus it is recommended that vulnerable patients, including those with HIV infection, be removed from direct contact with vaccine recipients until virus shedding has resolved. If a potential vaccinee has a household contact with HIV infection, vaccination is contra-indicated. The CDC recommends that the alternative is living apart, until public health officials state that there is no longer a risk, which is likely to be 10 -20 days following vaccination. Healthcare workers who provide for HIV-positive persons should be reassigned to furlough duties until the inoculation scab dislodges.

Finally, in the event that progressive vaccinia does develop, investigational treatment is available (in the USA) with informed consent. Treatment with vaccinia immunoglobulin (VIG) is recommended, although it has never been studied in a controlled trial. Availability of VIG in the US is controlled by the CDC. The dosage is 0.6ml/kg body weight administered I/M, or approximately 40 ml usually given over 24 – 36hrs. Cidofovir has shown in-vitro activity against vaccinia, and in-vivo activity in a rodent model. However in a study in which immunodeficient mice were challenged with cowpox, cidofovir failed to prevent death. There is no clinical experience of cidofovir treatment of vaccinia. The CDC recommends both VIG and cidofovir as treatments for severe reaction to smallpox vaccination.

While this article details the US plans for mass smallpox vaccination and its implications for people with HIV, the UK stance remains unclear. On 3 March 2003, the BBC carried a news story detailing concerns of a “senior government advisor” over government lethargy about a smallpox terror attack. It was claimed that inactivity was being shrouded as secrecy. Within hours Home Secretary David Blunkett explained that London’s ability to respond to a catastrophic terror attack would be tested in the next few weeks, in an exercise involving all the emergency services, which would cover mass evacuations and the ability to decontaminate affected areas. In the meantime concerns on this issue for HIV-positive individuals in the UK remain to be addressed.

The author wishes to thank his colleague Dr Nesrina Imami for useful comments and source information.

References

1. John G. Bartlett. Smallpox vaccination and patients with human immunodeficiency virus infection or acquired immunodeficiency syndrome. Clinical infectious diseases. Confronting biological weapons. 15 February, 2003; 36:468-71.
2. Public may force smallpox U-turn. BBC.
   http://news.bbc.co.uk/1/hi/health/2538249.stm
3. UK terror attacks exercise planned. BBC
   http://news.bbc.co.uk/1/hi/uk_politics/2814087.stm

Links:

Journal Infectious Diseases:
http://www.journals.uchicago.edu/CID/journal/issues/v36n4/30342/30342.html

Smallpox Vaccination and HIV Infection – Hopkins report Jan 2003
By John G. Bartlett, M.D.
http://www.hopkins-aids.edu/publications/report/report_toc_03.html