Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.
Vaccinia smallpox vaccine
lyophilised powder for reconstitution and injection
Approved indication: prevention of smallpox
Australian Medicines Handbook section 20.1
Previous vaccines have been effective in preventing smallpox, with the last case reported in Somalia in 1977. However, there are growing concerns that variola virus, which causes smallpox, may still be present in some laboratories and could be used as a biological weapon.
The disease is transmitted from human to human via saliva droplets. Most people recover from the infection caused by the Variola minor strain, but death can occur in up to a third of people infected with the Variola major strain.
This vaccine is a live attenuated vaccinia virus which cross-protects people against both strains of the variola virus. In contrast to the old vaccine which was grown in the skin of calves this vaccine is produced by growing the ACAM2000 virus clone (derived from the old vaccine strain) in tissue culture. It must be given percutaneously in the upper arm using 15 jabs of a bifurcated needle, by a health professional trained in the procedure. Skin preparation should not normally be performed before the injections. However, if the vaccination site is visibly dirty, wipe it with an alcohol swab and make sure it is completely dry before giving the vaccine. This is to prevent inactivation of the virus by alcohol. After vaccination, the virus causes a localised infection at the injection site. The development of a pustule indicates that the vaccine has induced protective immunity.
The vaccine comes in multi-dose vials. Once it has been reconstituted in 0.3 mL of diluent, each vial contains approximately 100 doses.
In a phase II study, the highest dose of ACAM2000 vaccine appeared to induce equivalent immune responses to the old vaccine strain.1 In another randomised trial of 90 people, the new vaccine was compared to the parent vaccine strain and to a similar vaccine derived from the ACAM1000 virus clone (1:1:1). All participants had developed a pustule at the injection site within a week of vaccination, but the mean erythema size was significantly larger with the old vaccine compared to the ACAM2000 and ACAM1000 vaccines (36 mm vs 18 mm and 22 mm). Viral shedding was measured by culturing swabs from the inoculation site for approximately six weeks after vaccination. In all groups, viral shedding peaked at 15 days and had stopped by six weeks when most lesions had healed.2
The new vaccine has also been compared to the old vaccine (3:1) in two phase III trials involving almost 3000 people - one trial enrolled people who had received a previous vaccine more than ten years earlier and the other enrolled vaccinia-nave individuals. In people receiving the vaccine for the first time, it elicited a major cutaneous reaction in most people and was non-inferior to the comparator (96% vs 99% of individuals). However, mean antibody titres to the new vaccine were not as high as those seen with the comparator and did not meet the criteria for non-inferiority. In previously vaccinated people, antibody responses were non-inferior to the comparator.
Itching and pain at the injection site, fatigue, lymph node pain, headache, malaise and myalgia have been reported by the majority of people who have received the vaccine.2There is a risk of cardiac events (including fatalities) with this vaccine. In clinical trials, there were ten cases of suspected myocarditis out of 2983 people. All of these events were in vaccinia-nave people and occurred between 9 and 20 days after vaccination. The risk of cardiac problems may be increased in people with heart conditions such as previous myocardial infarction, angina, congestive heart failure, cardiomyopathy, chest pain or shortness of breath during activity, and stroke or transient ischaemic attack. Similarly, people with at least three of the following risk factors for ischaemic coronary disease high blood pressure, elevated cholesterol, diabetes, first degree relative with a heart condition before the age of 50 and smoking have an increased risk of cardiac events with the vaccine.
Because live virus particles are shed from the pustule that forms after vaccination, infections can spread to other parts of the body. Accidental eye infections have been reported with the vaccine and may result in complications including keratitis, corneal scarring and blindness. People using corticosteroid eye drops are at increased risk of this. People with skin disorders, particularly eczema, have a higher risk of developing eczema vaccinatum.
The vaccine is contraindicated in individuals with severe immunodeficiency, such as people with cancer, HIV/AIDS or cellular or humoral immune deficiency, or those receiving immunosuppressive drugs, radiation therapy or alkylating agents. The vaccine is also not recommended for pregnant women because of the risk of fetal death, or in infants under one year. After vaccination, contact with individuals who have a high risk of complications should be avoided.
To prevent the spread of the vaccinia virus, patients should keep the injection-site wound covered until it heals, wash their hands after handling bandages and wash any contaminated clothing or bed sheets separately.
This vaccine may cause false-positives with syphilis testing. Positive results from the rapid plasma reagin (RPR) test should be confirmed by a more specific test such as the fluorescent treponemal antibody-absorbed (FTA) test. Similarly, the vaccine may induce false negative results with the tuberculin skin test so if this test is planned, it should be postponed for one month after smallpox vaccination. Blood and organ donation should be avoided for at least 30 days after vaccination.
This vaccine appears to be effective in inducing a cutaneous immune response similar to that seen with the older calf-derived vaccine, but antibody titres seem to be lower. There are some concerns about the cardiac safety of this vaccine.
Manufacturer provided the clinical evaluation
Note on references
At the time the comment was prepared, information about this drug was available on the web site of the Food and Drug Administration in the USA (www.fda.gov).
- Artenstein AW, Johnson C, Marbury TC, Morrison D, Blum PS, Kemp T, et al. A novel, cell culture-derived smallpox vaccine in vaccinia-nave adults. Vaccine 2005;23:3301-9.
- Frey SE, Newman FK, Kennedy JS, Ennis F, Abate G, Hoft DF, et al. Comparison of the safety and immunogenicity of ACAM1000, ACAM2000 and Dryvax in healthy vaccinia-nave adults. Vaccine 2009;27:1637-44.