Anthrax, Smallpox and Multiple Vaccinations: What We Know and Do Not Know

1. Anthrax, Smallpox and Multiple Vaccinations:What We Know and Do Not Know Omowunmi (‘Wunmi) Osinubi, MD, M.Sc., MBA, FRCA. Adjunct Assistant Professor Department of Occupational and Environmental Health UMDNJ-School of Public Health & Robert Wood Johnson Medical School Occupational Health Physician War Related Illness and Injury Study Center

2. Rationale for Military Vaccinations • Vaccines are important for military force health protection in peacetime and in war • Vaccines are administered to protect troops from infectious diseases that are common to US populations • Vaccines are intended to protect troops from serious/deadly diseases in deployment situations and/or from biological warfare agents

3. Military Service Vaccinations • Routine vaccinations are initiated during basic training • Boosters are administered periodically to maintain immunity for the duration of military service • Additional vaccines may be administered in special circumstances • Specific occupational groups as protection against infectious hazards associated with their job duties (e.g., medical & laboratory personnel) • Overseas deployments with particular endemic infectious diseases (e.g., typhoid, yellow fever e.t.c.) • Suspected biological warfare agents

4. Vaccines Routinely Administered to All Military Recruits (PGW)

5. Vaccines Administered to Special Military Occupations (PGW Era)

6. Risk of Dying

7. Biological Warfare Threats in Persian Gulf Conflicts • Intelligence reports suggested that troops were at risk from weaponized biological warfare agents in Iraq • Biological warfare agents of concern • Botulinum toxin • Smallpox • Anthrax

8. Biological Weapons (BWs) • Biological warfare • Employment in war of biological agents to injure or destroy people, animals, or crops • Dispersal of microbes or their toxins to cause widespread illness, death and terror. • Characteristics of BWs • Low visibility • High potency • Substantial accessibility • Relatively easy delivery

9. History of Biological Warfare • Use of BWs date back to antiquity • Prior to the 20th Century, there were 3 methods of BW • Deliberate poisoning of food and water • Roman literature from 300 BC - animal cadavers were used to contaminate wells • Biological agents/toxins on weapons system • Scythian archers infected their arrows by dipping them into decomposing bodies or blood mixed with manure – Circa 400BC • Biological agents inoculated on fabrics. • During the French & Indian War, British forces in North America gave blankets from small pox patients to native Americans to create transmission of the disease to immunologically naïve tribes.

10. History of Biological Warfare Contd. • In 1900s BW became more sophisticated. • During WWI, Germans developed anthrax, glanders, wheat fungus and cholera as BWs • In 1925, the Geneva protocol signed by 108 nations was the 1st multilateral agreement that extended prohibition of chemical & biological warfare agents. • No method for verification of compliance was addressed • WWII and through the 1970’s, Japan, USA, UK had active offensive biological weapons programs

11. Bioterrorism • Since 1980’s terrorist organizations have become users of biological agents • 751 persons were infected with Salmonella Typhimurium after intentional contamination of the salad bar in an Oregon restaurant by followers of Bhagwan Shree Rajneesh (1984) • Iraq began an offensive BWs program, producing anthrax, botulinum toxin, and aflatoxin in 1985 • After the Persian Gulf War, Iraq disclosed that it had bombs, Scud missiles, 122-mm rockets, and artillery shells armed with botulinum toxin, anthrax and aflatoxin. • Spray tanks fitted to aircrafts that could distribute 2000 L over a target

12. The Threat of Bioterrorism Still Exists • "The cold reality is that it is almost impossible to enforce the existing biological weapons treaty.There is no biological weapons facility, which if shut down today could not be rebuilt tomorrow," http://news-service.stanford.edu/news/january21/lederberg.html

13. Encephalitis Virus Tularemia Staph enterotoxin Brucella Ebola/Marbug Biological Warfare Agents of Concern • Anthrax • Botulinum Toxin • Smallpox • Plague • Ricin Toxin

14. Anthrax • Acute infectious disease • Spore-forming bacterium Bacillus anthracis • Anthrax spores remain viable in the soil for decades • Commonly occurs in wild and domestic animals including cattle, sheep, goats, camels, antelopes and other herbivores • Incidence of naturally occurring anthrax in the US is approximately one case per year The Anthrax Letters

15. Clinical Features of Anthrax • Cutaneous anthrax • Small papule, which progresses to an ulcer with black eschar • More than 95% of cases of anthrax are cutaneous • Lesion usually heals in 2-3 weeks • Septicemia is rare • Mortality rate is 1% if there is adequate treatment • Gastrointestinal anthrax • Transmission is from ingestion of infected meat • Nausea, vomiting, fever, tonsilar enlargement, severe abdominal pain, respiratory distress, acute abdomen, massive ascites & diarrhea • Mortality rate 50% • Meningitis

16. Pulmonary Anthrax • “Woolsorter’s disease” • Fever, malaise, fatigue, myalgia, respiratory distress which may be followed by onset of shock and death within 24-36 hrs. • Inhalational anthrax is the most likely form of disease to follow military or terrorist attack • Such an attack likely will involve aerosolized delivery of anthrax spores • Mortality rate is 80-90%, but may approach 100% if septic shock. • Of the 11 cases of inhalational anthrax in the 2001 bioterrorism attacks in the US, only 6 patients survived (65% survival rate)

17. Smallpox • Variola is the most notorious of the poxviruses • Highly infectious by aerosol • Environmentally stable • Retains infectivity • Represents a significant threat as a BW agent • Smallpox is believed by some to have been responsible for the death of more people than any other acute infectious disease. • 1980 - WHO declared that endemic small pox had been eradicated. • Last known case of smallpox was in Somalia in 1977

18. Clinical Features of Smallpox • Systemic viral disease • high fever, headaches, myalgias, vomiting, abdominal & back pain • skin lesions • Variola major • 30% case fatality rate in unvaccinated persons • 3% fatality rate in previously vaccinated persons.

19. Botulinum Toxins (BTs) • BTs are the most lethal toxin known • 10,000 – 100,000 times more toxic than chemical nerve agents • 1 gm crystalline BT can kill > 1 million people if dispersed and inhaled evenly • 0.001 mcg/kg will kill 50% of the exposed population (LD50) • Point source aerosol release • Incapacitate/kill 10% of people downwind within 500 meters (0.3 miles) Clostridium botulinum

20. Botulinum Toxin Warfare • Credible threat as BW agent • Extreme potency and lethality • Ease of production • Ease of transport • Need for prolonged intensive care • 1991- Iraq weaponized 19,000L of BT during Persian Gulf War • 1995 - Iraq admitted to weaponizing and deploying more than 100 munitions with BT

21. Mechanism of Action of BT • BT binds to the pre-synaptic terminal of the neuromuscular junction & cholinergic autonomic sites • Prevents release of acetylcholine • Causes muscular weakness & paralysis • Recovery requires months for the neurons to develop new axons

22. Clinical Features of Botulism • Classic Triad • Symmetric, descending flaccid paralysis with prominent bulbar palsies • Bulbar palsies • Diplopia, dysarthria, dysphonia, dysphagia • (four D’s) • Afebrile • Clear sensorium – normal mental status exam • Most serious complication of toxicity is respiratory failure • With adequate supportive care, mortality rate is <5% • Recovery could take months.

23. Botulism Patient at rest, bilateral mild ptosis, disconjugate gaze, symmetric facial muscles. Requested to perform max. smile. Ptosis, disconjugate gaze, mild asymmetric smile. JAMA. 2001;285:1059-1070

24. Risk of Dying

25. Mandatory Military Vaccinations • The military first mandated immunizations in 1777 • General Washington required troops to receive small pox vaccines • Since then small pox vaccine has been given to service members during major conflicts • Small pox vaccination was suspended in 1990 • DOD mandated vaccinations for anthrax and smallpox in 1998 and then in 2002out of concern of BW threats • At time of PGW, new recruits received up to 17 antigens during the first 2 weeks of basic training

26. Vaccination Adverse Effects • No immunization is completely safe • Some service members who received these vaccines have developed severe reactions which they are attributing to vaccines • Migraines, heart problems, diabetes • multiple sclerosis, medically unexplained neuromuscular and musculoskeletal problems • Questions have been raised about effects of receiving multiple vaccinations over a short period of time versus reaction to any single vaccine • Case reports of similar health problems in soldiers who received the vaccines but did not actually deploy.

27. Bio-warfare Vaccines

28. BotulinumToxoid (BT) • Pentavalent BT vaccine was still an investigational vaccine • BT was administered to fixed units, forward deployed troops in PGW • Schedule was 3 shots over 12 weeks • An estimated 12% of Gulf war vets received BT • DOD estimates that 137,850 BT doses were administered in theater • 8,000 individuals received at least one dose of BT • Vaccine efficacy trials in the 1960’s • Few problems with acute local reactions • No problems with severe systemic reactions • CDC monitoring data of 17,000 doses administered prior to 1997 • 7% had moderate local reaction • 0.4% severe reaction • Health events were of limited duration

29. Smallpox Vaccine • Vaccination is safe & effective for most people • Mild symptoms • Local soreness & redness • Enlarged regional lymph nodes • low fever • 1 out of 3 people may feel unwell enough to miss work • Serious reactions • Vaccinia rash - localized or widespread (generalized vaccinia) • Toxic allergic rash to the vaccine (erythema multiforme) • 1 in 1000 recipients

30. Smallpox Vaccine Contd. • Life-threatening reactions • Eczema vaccinatum • Widespread severe skin infection in persons with eczema or atopic dermatitis • Vaccinia necrosum • Extensive tissue destruction leading to death • Post-vaccinal encephalitis • Recent developments • Causal association between vaccination & myocarditis • Angina & heart attack have been reported post-vaccination • Persons with post-vaccination chest pain, shortness of breath or cardiac disease must seek medical attention ASAP.

31. Anthrax Vaccine (AVA) • AVA was licensed in 1970 • Alumnium hydroxide-adsorbed preparation • Vaccination series comprised 6 subcutaneous injections over 18 months • 0, 2 & 4 weeks; 6, 12 and 18 months; annual boosters • Studies in rhesus monkeys indicate that AVA is protective of inhalational anthrax • Very limited human vaccine efficacy data

32. AVA Immunization Policies (PGW) • There was not enough time or adequate AVA supplies to vaccinate all the troops in time for deployment • US Central Command (CENTCOM) recommended & designated vaccination process as follows: • 2 shots, 2 weeks apart; “low-profile” vaccination process • Fixed units & rear deployed troops • Personnel in Riyadh, Dharan-Damman areas, King Khalid Military City, Logistic Bases A, B, C, D, E, Army VII Corps HQ, Army XVII Airborne Corps HQ, Bahrain, 1st Calvary Division • 310,680 doses were administered in theater • 150,000 troops received one or more shots • 41% of all US vets; 30% of Navy Seabees reported receiving AVA

33. AVA – Public Perception • Media controversy and public debate fueled by several factors ? Efficacy against inhalational anthrax ? Manufacturing quality control problems ? Short and long-term side effects ? Vaccine components and adjuvants “Squalene” vs Aluminium hydroxide hypotheses ? Military policies that first mandated vaccinations, punished refusals for vaccinations and later retracted mandatory vaccination ? Indications for vaccinations was not uniformly applied ? Vaccinations performed in “secrecy”, inadequate informed consent, and incomplete documentation of anthrax vaccinations ? Variability in vaccines used • Differences in vaccines used prior to the 1970s versus Gulf war vaccines • Differences in US versus UK military vaccines • Differences in reactions/adverse effects associated with different lots of the AVAs

34. With Permission -http://www.johnlund.com/page.asp?ID=2154

35. Short-term Health Effects of AVA • Clinical trials of 1,250 recipients done in the 1950’s • Acute local reaction in 35% • Less than 3% of which were severe • CDC unpublished data of 7,000 recipients used for licensure in 1970 (cited by the 2002 IOM report on AVA) • Mild reaction in 8%; severe reactions in 0.2% • Reanalysis of a subset of data of 1750 recipients • Mild local reactions in 28% of doses • Women were 3X more likely than men to have reactions • Post -1998 AVA studies showed much higher rates of local and systemic reactions compared to other vaccines • Local reactions 70-80% • Redness, swelling, burning, lump, soreness • Systemic reactions 10-40% • Headaches, myalgia, malaise, joint pain, fatigue • Veterans who had acute reactions to deployment-related vaccines, tended to be in poor health years after the war.

36. Long-term Health Effects of AVA • Earlier studies of AVA provided little information regarding long-term health effects • Individual case reports • Immediate & delayed hypersensitivity reactions, rheumatoid arthritis, optic neuritis, lymphocytic vasculitis, oral pemphigus vulgaris, and demyelinating diseases including multiple sclerosis • Summary of VAERS data for AVA • Two studies indicate that AVA had more joint symptoms & GIT problems reported relative to the other vaccines. • The Vaccine Adverse Event Reporting System (VAERS) is a passive surveillance system • More recent studies - large military health services utilization data • Compared rates of hospitalizations, clinic visits, and disability for diagnosed conditions at 6 weeks to 4 yrs post AVA in troops vs. non-vaccinated troops • To date, studies have found few differences in AVA recipients vs. non-recipients

37. Gaps in Current Knowledge • Current health services utilization research data have inherent limitations that preclude generalization of research findings • Healthy worker effect • Combat ready troops are generally in better fitness and are more likely to have received AVA compared with persons with pre-exisiting disabilities or medical problems • Inclusion of only vets who utilized military health service • Excludes persons who left military service – particularly those medically discharged or felt too unwell to continue service • Excludes health conditions that are not severe enough for hospitalization, but are incapacitating nonetheless • Follow-up periods insufficient to detect health problems that have a long latency period

38. Summary • Veterans deployed to the Persian Gulf received multiple vaccinations for force protection purposes • AVA is the most controversial of these vaccines • There is paucity of empiric research that provides adequate information about rates of persistent symptoms or multi-symptom illness post anthrax and/or other vaccinations

39. Considerations for Future Research • Establish a comprehensive database of all Veterans deployed to the Persian Gulf • To the extent feasible, obtain deployment exposure history and current health concerns. • Cohort and/or case-control studies would be helpful to determine whether individual vaccines and/or combinations of vaccines are independent predictors of health problems in Veterans deployed to the Persian Gulf. • Conduct more definitive studies in non-deployed Veterans who received the vaccines versus non-deployed non-recipients, versus deployed vaccine recipients

40. So Why Should We Careabout Veterans’ Vaccination concerns?

46. So why should we careabout Veterans’ vaccination concerns? Because they cared for us

48. References Authier FJ, Sauvat S, Champey J, Drogou I, Coquet M, Gherardi RK. Chronic fatigue syndrome in patients with macrophagic myofasciitis. Arthritis Rheum. 2003;48:569-570. Centers for Disease Control and Prevention. SMALLPOX FACT SHEET. Side Effects of Smallpox Vaccination. http://www.bt.cdc.gov/agent/smallpox/vaccination/reactions-vacc-public.asp Cherin P, Gherardi RK. Macrophagic myofasciitis. Curr Rheumatol Rep. 2000;2:196-200. Dire DJ. CBRNE - Biological Warfare Agents. http://emedicine.medscape.com/article/829613-overview Geier DA, Geier MR. Anthrax vaccination and joint related adverse reactions in light of biological warfare scenarios. Clin Exp Rheumatol. 2002;20:217-220. Geier MR, Geier DA. Gastrointestinal adverse reactions following anthrax vaccination: an analysis of the Vaccine Adverse Events Reporting System (VAERS) database. Hepatogastroenterology. 2004;51:762-767. Gherardi RK, Coquet M, Cherin P, et al. Macrophagic myofasciitis lesions assess long-term persistence of vaccine-derived aluminium hydroxide in muscle. Brain. 2001;124:1821-1831.

49. References Contd. Petrik MS, Wong MC, Tabata RC, Garry RF, Shaw CA. Aluminum adjuvant linked to Gulf War illness induces motor neuron death in mice. Neuromolecular Med. 2007;9:83-100. Research Advisory Committee on Gulf War Veterans’ Illnesses. Gulf War Illness and the Health of Gulf War Veterans: Scientific Findings and Recommendations. Washington, D.C.: U.S. Government Printing Office, November 2008 Steele L. Prevalence and patterns of Gulf War illness in Kansas Veterans: association of symptoms with characteristics of person, place, and time of military service. Am J Epidemiol. 2000;152:992-1002. Takafuji ET, Russell PK. Military immunizations. Past, present, and future prospects. Infect Dis Clin North Am. 1990;4:143-158. U.S. Department of Defense, Office of the Special Assistant for Gulf War Illnesses. Information Paper: Vaccine Use During the Gulf War. Washington, D.C. Dec 7, 2000. United States Government Accountability Office. GAO-07-787R DOD’s health care Centers Network. Washington DC, June 2007. http://www.gao.gov/new.items/d07787r.pdf Wells TS, Sato PA, Smith TC, Wang LZ, Reed RJ, Ryan MA. Military hospitalizations among deployed US service members following anthrax vaccination, 1998-2001. Hum Vaccin. 2006 Mar-Apr;2(2):54-9. Epub 2006 Mar 13.