Established Safety Surveillance for Smallpox Vaccine

Smallpox Vaccine Adverse Events Monitoring Needs (22:V7:17)

Monitoring for vaccine adverse events in a pre-outbreak vaccination program verses a post-event outbreak control emergency vaccination program will be different.

Pre-outbreak program should focus on assuring the best possible safety profile for the vaccine, characterize non-serious and serious AE profiles to assist with post-event response planning, education, etc., identify all unexpected AEs, instill confidence in program by assuring that careful monitoring is being done and enhancing strategies to screen for persons with contraindications to vaccination.

Post-event outbreak AE monitoring may have to be adjusted to accommodate large numbers of people being vaccinated in a short period of time. Emergency response mode, limited resources, must focus on immediate needs such as identifying most serious AEs that require medical resources.

Pre-Outbreak Smallpox Vaccine AE Monitoring (22:V7:18)

A pre-event program has to be as safe as possible as you are vaccinating people for a disease that doesn’t exist naturally anymore and for an un-definable risk of future exposure. It should screen out people who may have potential problems, even if you would normally allow vaccination in outbreak setting (e.g. people without definite risk factors but who may have questionable risk factors).

At least in early stages of program, a pre-event program must have a timely and responsive system for monitoring in order to pick up problems quickly. The program must also be able to treat individuals with limited access medications (VIG) if needed. A successful pre-event program needs to maintain confidence that authorities are being as vigilant as possible to assure a safe program.

Additional studies to define full scope of AEs (common and minor to more serious) in current, older primarily vaccinated population so that will have a better idea of what to expect in a post-event emergency response vaccination program. The pre-event program will also assist with training and education for post-event response. An opportunity to “test-run” system in non-emergency setting to identify needs to address in larger-scale post-event monitoring system is also an important part of a pre-event program.

The pre-outbreak setting also provides the opportunity to monitor any adverse events resulting from the treatment of vaccine adverse events using VIG or Cidofovir. Thus, we would have a comprehensive safety profiles on the vaccine and AE treatments.

Safety Steps at Time of Vaccination (22:V7:19)

In order to help prevent adverse events from occurring in the first place, participants should be carefully screened for contraindications. Participants should be given extensive instructions on contraindications, adverse events and where to seek evaluation, and site care before vaccination.

Recognition of a Problem Individual (22:V7:20)

Given the lack of experience with smallpox vaccine in most healthcare communities, even recognizing people who are having adverse events may be difficult. The key for the pre-outbreak monitoring system is to be overly sensitive. Vaccinees need to be told that they should have any unexpected symptoms or serious side effects evaluated by a physician, and vaccine recipients should be encouraged to report to the vaccination clinic or healthcare provider if the vaccine site looks worse that the pictures they are given of the expected vaccine take. Anyone who develops more than the expected mild systemic illness expected is also encouraged to call in.

Response to a Problem Individual (22:V7:21)

When a significant individual problem is identified/reported, vaccine safety team personnel should begin an investigation; ensuring that a VAERS form has been submitted and is filled out completely. More serious adverse events would be referred to the established CDC Clinical specialist who can consult on various aspects of vaccine adverse events. The vaccine recipient is followed until the adverse event has resolved and then for as long a year after depending upon the vaccine complication.

Recognition of a Problem Population [Population: unusual reactions or high rates] (22:V7:22)

At the national level, the CDC and the FDA reviews all the VAERS forms submitted for smallpox vaccine. The CDC also reviews the follow-up information obtained by the Clinical Consultation team. The CDC routinely calculates rates and monitors for unusual reactions. This data is further monitored by an expert committee composed of the Advisory Committee on Immunization Practices (ACIP), Department of Defense (DoD) members, and smallpox experts. The vaccination program overall is monitored by the Institute of Medicine.

Recognition of a Problem Population Response (22:V7:24)

If a problem is identified, the CDC will begin an investigation to determine if this indicates a previously unknown contraindication, or some issue with screening criteria. This is also an opportunity to review other possible causes of the condition and to possibly improve the vaccine. The response includes:

  1. Identify groups at risk for VAE; new contraindications, screening for contraindications not consistent, unavoidable VAEs (e.g. person with contraindication was also high-risk contact in post-outbreak setting).
  2. Determine if VAEs differ by lot, clinic, etc.
  3. Determine if AE resulted from treatment of vaccine reaction (e.g. renal failure from Cidofovir).
  4. Investigate pathophysiology of VAE.
  5. Develop new, safer vaccine.

Smallpox Vaccine Safety Workgroup/Advisory Committee on Immunization Practices

To provide an additional level of oversight, a committee of clinical experts can review data on a regular basis in order to monitor the program and help to formulate medical policy. It is composed of a standing committee of clinical and public health experts from the CDC’s immunization advisory group, DoD’s Armed Forced Epidemiology Board and other designated smallpox experts and specialty consultants. The workgroup functions as medical monitor for smallpox vaccine program as IND protocols (VIG and Cidofovir). They review and assess VAE data from multiple sources (VAERS, Diary Cards, Epidemiology Studies), as well as AEs associated with IND medications for treatment of smallpox vaccine AEs.

Post-Outbreak Smallpox Vaccine AE Monitoring (22:V7:25)

The ability to monitor AEs in a post-event emergency setting will most likely be limited and must focus on the more serious adverse events that require utilization of medical resources. One of the post-outbreak tasks is adapting pre-existing monitoring system to meet increased demands and post-event priorities. Since those using the monitoring system would be more familiar with existing systems, it makes sense to modify those existing systems than to have people learning a new system under the duress of an outbreak. Another task is to establish monitoring system priorities. Identification and immediate reporting of serious, known AEs requiring hospitalization and/or treatment (VIG) would be a top priority. Also, the identification and immediate reporting of serious unexpected AEs would also be a high priority. Establishing a method and frequency of data communication: Web-based, Publications, or Daily or weekly totals.

Smallpox Vaccine Safety System

The following information is a detailed description of the current, pre-outbreak responder smallpox vaccine safety monitoring program in the United States. (22:V7:26-41)

During the early phases of smallpox vaccination, vaccination clinics and healthcare providers should report clinically significant and unexpected adverse events to their state health department. The state health department will, in turn, report such adverse events to the CDC. A VAERS report should also be filed for clinically significant and unexpected adverse events. The VAERS report can be submitted by the clinic, provider, vaccinee, or state health department. Although any adverse event can be reported to VAERS, it is most important to report the clinically significant or unexpected adverse events, ideally within 48 hours. Clinically significant being; serious adverse events, events that result in death, hospitalization, permanent disability, or are life-threatening. Adverse events that prompt a visit to a healthcare provider may also be considered clinically significant; however, that is left to the judgment of the healthcare provider. Adverse events other than unexpected or clinically significant can be reported to VAERS within 7 days.

Smallpox Adverse Events to Report:

  1. Eczema vaccinatum
  2. Erythema Multiforme major/Steven Johnson
  3. Fetal vaccinia
  4. Generalized vaccinia
  5. Inadvertent inoculation
  6. Myocarditis/pericarditis
  7. Ocular vaccinia
  8. Post vaccinial encephalitis
  9. Progressive vaccinia
  10. Pyogenic infection of vaccination site
  11. Vaccinia transmission to contacts
  12. Vaccination of person with a contraindication
  13. Other serious AEs and any AE of concern to a clinician/patient

Reporting Adverse Events Following Smallpox Vaccine

Anyone can report to VAERS: vaccinees, healthcare providers, vaccine manufacturers, and, of course, state health departments. For smallpox vaccine, state health departments should make sure that VAERS reports have been filed for the clinically significant and unexpected adverse events. Reports can be sent to VAERS via the web, FAX, or mail.

Federal Health Authorities (CDC) Roles and Responsibilities

Vaccine safety roles and responsibilities of the different participants in the vaccine program:

  1. At the Federal level, CDC is responsible for tabulating the reported adverse events, by number and type of adverse event, determining the reported frequency of known serious adverse events to estimate whether the reported rates are consistent with the historically reported rates, and reviewing VAERS reports and information from the states and providers on a daily basis to monitor for unexpected adverse events.
  2. If there are any unusual adverse events, such as type of event, geographic location, or population distribution, CDC will conduct special studies to further investigate any risk factors.
  3. CDC will make Vaccinia Immune Globulin or VIG and Cidofovir available under Investigational New Drug (IND) protocols for selected adverse events.

CDC provides technical assistance to state public health authorities to support the safest possible use of smallpox vaccine. For example, CDC provides assistance for questions regarding screening, contraindications, vaccination technique, and adverse events. CDC will also provide technical consultation to clinicians in the diagnosis and management of adverse events after smallpox vaccination, especially if the adverse events are moderate to severe, unexpected, or are not following an expected clinical course. CDC works directly with the Food and Drug Administration (FDA) to closely monitor VAERS reports.

State Health Authorities Roles and Responsibilities

State Health authorities are responsible for developing a plan to assure monitoring of adverse events among vaccinees (state-based response team members) in their state smallpox vaccination program. As part of that plan, State Health authorities must identify an individual to oversee, establish, and coordinate state vaccine safety monitoring. State Health Authorities must communicate with medical organizations, media, and public on vaccine safety issues before, during, and after the vaccination program.

Although states may designate or recommend certain medical facilities for the assessment of adverse events, in practice, vaccinees could enter the healthcare system at many points. Therefore, should make sure healthcare providers are aware of the vaccination program and know who to contact if they need to assess, refer, or treat a person with a potential vaccine adverse event.

At the state/local level a system should be developed for rapid reporting and local assessment of adverse events in vaccinees or their contacts. This system should provide coverage for answering questions posed by vaccinees and clinician 24 hours a day, 7 days a week. This system should assure prompt reporting to Federal officials (CDC) for clinically significant and unexpected adverse events; VIG or Cidofovir requests; and for the clinical outcome following treatment.

Hospital Roles and Responsibilities

The hospitals with smallpox response teams must provide follow-up of their own team vaccinees, including 24/7 coverage for vaccine adverse event assessment. Hospitals should identify subspecialists to assist with assessment of suspected adverse events in other persons who may present for evaluation. Subspecialty categories would ideally include: Dermatology, Infectious diseases, Neurology, Ophthalmology and Allergy/Immunology.

Hospital staff should know the system and requirements for reporting AEs to the state health authorities and requesting VIG and other treatments or recommendations for serious AEs. Hospitals should promptly notify their state health department of any clinically significant or unexpected adverse events and should submit a case report to the health department.

Vaccine Clinic Roles and Responsibilities

Vaccination clinics should be prepared to treat rare, immediate adverse events, such as anaphylaxis or syncope. The clinics should be able to educate vaccinees on vaccination site care, such as with written instructions. Vaccine clinics should assure that vaccinees have instructions for follow up, such as for vaccine take checks.The clinics should know the reporting process for adverse events for their own reporting purposes, and should also provide vaccinees with information on who to contact for suspected adverse events. Clinics should keep track of the number of persons vaccinated. This is helpful for evaluating clinic operations, monitoring vaccine use, and, for vaccine safety purposes, it facilitates calculating the rate of reported adverse events.

Individual Providers Roles and Responsibilities

Individual health care providers should at least be able to recognize possible smallpox vaccine adverse events. Many of the adverse events will be mild and can be managed by primary care physicians. For moderate, severe, or unusual adverse events, healthcare providers should know how to refer patients as clinically indicated to an appropriate specialist. For clinically significant and unexpected adverse events, the provider must report to the state health department and to VAERS. If a provider needs to treat a vaccinee or contact with VIG or Cidofovir, the provider must seek consultation with Federal authorities and comply with the IND protocol requirements for the administration of these medications. 

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