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

1
Anthrax, Smallpox and Multiple VaccinationsWhat
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)
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
5
Vaccines Administered to Special 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 months then booster every 1-2 years
 Smallpox  Vaccine or booster to new recruits through the late 1980s  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
6
Risk 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 1990s One in 50,000,000
Anthrax in 2001 One in 50,000,000
Smallpox in 2001 Less than One in 50,000,000
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 1970s, Japan, USA, UK had
  active offensive biological weapons programs

11
Bioterrorism

• Since 1980s 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
Biological Warfare Agents of Concern

• Anthrax
• Botulinum Toxin
• Smallpox
• Plague
• Ricin Toxin

• Encephalitis Virus
• Tularemia
• Staph enterotoxin
• Brucella
• Ebola/Marbug

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

• Woolsorters 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 gt 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 Ds)
• Afebrile
• Clear sensorium normal mental status exam
• Most serious complication of toxicity is
  respiratory failure
• With adequate supportive care, mortality rate is
  lt5
• Recovery could take months.

23
Botulism
Requested to perform max. smile. Ptosis,
disconjugate gaze, mild asymmetric smile.
Patient at rest, bilateral mild ptosis,
disconjugate gaze, symmetric facial muscles.
JAMA. 20012851059-1070
24
Risk 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 1990s One in 50,000,000
Anthrax in 2001 One in 50,000,000
Smallpox in 2001 Less than One in 50,000,000
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
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 1960s
• 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?
ID2154
35
Short-term Health Effects of AVA

• Clinical trials of 1,250 recipients done in the
  1950s
• 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?
41
(No Transcript)
42
(No Transcript)
43
(No Transcript)
44
(No Transcript)
45
(No Transcript)
46
So why should we careabout Veterans vaccination
concerns?
Because they cared for us
47
(No Transcript)
48
References

• Authier FJ, Sauvat S, Champey J, Drogou I, Coquet
  M, Gherardi RK. Chronic fatigue syndrome in
  patients with
• macrophagic myofasciitis. Arthritis Rheum.
  200348569-570.
• Centers for Disease Control and Prevention.
  SMALLPOX FACT SHEET. Side Effects of Smallpox
  Vaccination.
• http//www.bt.cdc.gov/agent/smallpox/vaccination/r
  eactions-vacc-public.asp
• Cherin P, Gherardi RK. Macrophagic myofasciitis.
  Curr Rheumatol Rep. 20002196-200.
• Dire DJ. CBRNE - Biological Warfare Agents.
  http//emedicine.medscape.com/article/829613-overv
  iew
• Geier DA, Geier MR. Anthrax vaccination and joint
  related adverse reactions in light of biological
  warfare
• scenarios. Clin Exp Rheumatol. 200220217-220.
• Geier MR, Geier DA. Gastrointestinal adverse
  reactions following anthrax vaccination an
  analysis of the
• Vaccine Adverse Events Reporting System (VAERS)
  database. Hepatogastroenterology.
  200451762-767.
• Gherardi RK, Coquet M, Cherin P, et al.
  Macrophagic myofasciitis lesions assess long-term
  persistence of
• vaccine-derived aluminium hydroxide in muscle.
  Brain. 20011241821-1831.

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.
  2007983-100.
• 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.
  2000152992-1002.
• Takafuji ET, Russell PK. Military immunizations.
  Past, present, and future prospects. Infect Dis
  Clin North
• Am. 19904143-158.
• 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 DODs health care Centers Network.
  Washington DC,
• June 2007. http//www.gao.gov/new.items/d07787r.pd
  f
• Wells TS, Sato PA, Smith TC, Wang LZ, Reed RJ,
  Ryan MA. Military hospitalizations among deployed
  US service