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Anthrax, Smallpox and Multiple Anthrax, Smallpox and Multiple Vaccinations:Vaccinations:
What We Know and Do Not KnowWhat 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 PhysicianWar Related Illness and Injury Study Center
Rationale for Military Rationale for Military VaccinationsVaccinations
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
Military Service VaccinationsMilitary 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
Vaccines Routinely Vaccines Routinely Administered to All Military Administered to All Military
Recruits (PGW)Recruits (PGW)Vaccine Schedule
Adenovirus 1 oral dose
Influenza Annual shot
Measles 1 shot
Meningococcal 1st shot & booster every 3-5 years
Polio 1 oral dose
Tetanus-Diptheria Booster every 10 years
Rubella I shot
Small pox (through the late 1980s)
1 dose
Vaccines Administered to Special Vaccines Administered to Special Military Occupations (PGW Era)Military Occupations (PGW Era)
Vaccine Personnel Schedule
Plague Marines, Navy, Army, Special forces, at-risk occupations or deployment to at risk areas
5 shots over 12 monthsthen booster every 1-2 years
Smallpox Vaccine or booster to new recruits through the late 1980’s
1 dose
Typhoid Army & Air Force alert forces for deployment to high risk areas
2 doses in 2 months, then booster every 3 years
Yellow Fever Navy, Marines, Army and Air Force alert forces and for deployment to high risk areas
1st shot, then booster every 10 years
Risk of DyingRisk of Dying
Smoking 10 cigarettes a day One in 200
Road accident One in 8,000
Playing soccer One in 25,000
Homicide One in 100,000
Terrorism attack in 2001 One in 100,000
Hit by lightning One in 10, 000,000
Terrorism attack in 1990’s One in 50,000,000
Anthrax in 2001 One in 50,000,000
Smallpox in 2001 Less than One in 50,000,000
Biological Warfare Threats in Biological Warfare Threats in Persian Gulf ConflictsPersian 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
Biological Weapons (BWs)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
History of Biological WarfareHistory 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.
History of Biological Warfare History of Biological Warfare Contd.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
BioterrorismBioterrorism 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
The Threat of Bioterrorism The Threat of Bioterrorism Still ExistsStill 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
Biological Warfare Agents Biological Warfare Agents of Concernof Concern
Anthrax Botulinum Toxin Smallpox Plague Ricin Toxin
Encephalitis Virus Tularemia Staph enterotoxin Brucella Ebola/Marbug
AnthraxAnthrax
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
Clinical Features of AnthraxClinical 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
Pulmonary AnthraxPulmonary 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)
SmallpoxSmallpox
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
Clinical Features of Clinical Features of SmallpoxSmallpox
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.
Botulinum Toxins (BTs)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
Botulinum Toxin WarfareBotulinum 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
Mechanism of Action of BTMechanism 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
Clinical Features of BotulismClinical 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.
BotulismBotulism
Requested to perform max. smile. Ptosis, disconjugate gaze, mild asymmetric smile.
Patient at rest, bilateral mild ptosis, disconjugate gaze, symmetric facial muscles.
JAMA. 2001;285:1059-1070
Risk of DyingRisk of Dying
Smoking 10 cigarettes a day One in 200
Road accident One in 8,000
Playing soccer One in 25,000
Homicide One in 100,000
Terrorism attack in 2001 One in 100,000
Hit by lightning One in 10, 000,000
Terrorism attack in 1990’s One in 50,000,000
Anthrax in 2001 One in 50,000,000
Smallpox in 2001 Less than One in 50,000,000
Mandatory Military Mandatory Military VaccinationsVaccinations
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
Vaccination Adverse EffectsVaccination 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.
Bio-warfare VaccinesBio-warfare Vaccines
Botulinum Toxoid (BT)Botulinum Toxoid (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
Smallpox VaccineSmallpox 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
Smallpox Vaccine Contd.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.
Anthrax Vaccine (AVA)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
AVA Immunization Policies AVA Immunization Policies (PGW)(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
AVA – Public PerceptionAVA – 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
With Permission -http://www.johnlund.com/page.asp?ID=2154
Short-term Health Effects of AVAShort-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.
Long-term Health Effects of Long-term Health Effects of AVAAVA 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
Gaps in Current KnowledgeGaps 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
SummarySummary
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
Considerations for Future Considerations for Future ResearchResearch
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
So Why Should We CareSo Why Should We Careabout Veterans’ Vaccination about Veterans’ Vaccination
concerns?concerns?
So why should we careSo why should we careabout Veterans’ vaccination about Veterans’ vaccination
concerns?concerns?
Because they cared for usBecause they cared for us
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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.
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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.
References Contd.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.
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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
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