National Manual for Surveillance of Adverse Events Following Immunization in Saudi Arabia

​

Prior to the COVID19 pandemic, vaccines were largely used to protect individuals particularly children from acquiring deadly infectious diseases which are preventable. Such products are relatively safe and can rarely cause serious adverse events following immunization (AEFI). A proportion of these vaccinations were provided during immunization campaigns when vaccinating large populations in a short period or when new vaccines are introduced. The COVID19 Pandemic changed the approach to vaccination by broadening the age groups vaccinated, the profile of vaccinators and the places where vaccinations take place. It also forced the global community to rethink the previous strategies and focus on having national AEFI surveillance systems in place that would be flexible and prepared to brand new vaccines that are rapidly deployed.

The “Immunization Agenda 2030[1]" focuses on a world where everyone, everywhere, at every age fully benefits from vaccines. The idea is to reduce mortality and morbidity from vaccine-preventable diseases for everyone throughout the life course leaving no one behind, by increasing equitable access and use of new and existing vaccines. The Global Vaccine Safety Blueprint 2.0 emphasizes on an accountability framework in which vaccine safety systems move from a minimal/ enhanced capacity concept to a maturity level concept.

The global reach of rare diseases in the past decade has increased. This includes Monkeypox, Ebola, Zika, SARS, MERS and other diseases for which new vaccines have to be/ are being developed and rapidly introduced. This implies that the AEFI surveillance systems for these evolving vaccination scenarios need to be rapidly upgraded and adapted to keep pace with the emerging context. Several countries have already introduced vaccines such as IPV and HPV in LMIC's national programs and there is also the probable introduction of newly developed vaccines such as malaria, dengue, Japanese encephalitis, typhoid conjugate vaccine in a larger scale. Thus, rapidly establishing credible AEFI surveillance systems becomes critical.

AEFI surveillance system in Saudi Arabia focuses on vaccine safety and it utilizes tools, guidelines and procedures geared to assure public health protection through the use of vaccines with proven safety profile.

In Saudi Arabia, the Expanded Programme on Immunization (EPI) which was established in 1974, has been involved in increasing immunization coverage to all age groups in the country. Saudi Arabia envisions a vaccine safety system with national dedicated vaccine pharmacovigilance capacity, with designated staff, with clear mandates and well-defined structures and roles.

The Saudi Food and Drug Authority (SFDA) and the Ministry of Health (MOH) in Saudi Arabia have collaborated to improve the quantity and quality of AEFIs reporting and patient care and safety in relation to the use of Vaccine.

The SFDA and the MOH have integrated the Saudi Vigilance System (SVS) and the MOH System, which collect data on adverse events following immunization (AEFIs). This integration has made it potential to collect more comprehensive data on AEFIs to identify and respond to potential risks associated with Vaccines.

Currently NIP and SFDA are in the process of establishing coordinating mechanisms for sharing vaccine safety data with the Global community through the WHO Programme for International Drug Monitoring.

By bringing these important stakeholders together, as well as engaging healthcare providers at all levels, the AEFI surveillance system will be well coordinated and vaccines will be effectively monitored for safety. This will contribute to assessing risks, benefits and effectiveness of vaccines thus minimizing harm and risks while maximizing known benefits.

An effective and well-functioning AEFI surveillance system will eventually boost trust, public confidence and will also help improve the quality of the immunization programme in the long run. It is therefore essential that all stakeholders like NIP, SFDA, vaccine manufacturers, laboratories and healthcare providers make concerted efforts to provide documented evidence through an effective AEFI surveillance system. This will ensure that the best immunization services are being provided to the community including effective monitoring and response to AEFIs.

This manual was developed in line with the WHO's Global Manual on Surveillance of AEFI aligned with the Immunization Agenda 2030's Strategic Priority 1, Immunization programmes for primary health care and universal health coverage with the objective of establishing and maintaining a well-functioning vaccine safety system involving all stakeholders. It is important to ensure that national immunization programmes can detect and respond to any concern about vaccine safety by continuous monitoring and coordination among relevant stakeholders

It is envisaged that this document will guide stakeholders at all levels to be involved in and take part in the strengthening of the AEFI surveillance system in Saudi Arabia.

Readers are also requested to provide inputs and suggestions that will be used when revising and adapting the manual in the future.

[1] https://www.immunizationagenda2030.org/ ​

Saudi Arabia wishes to acknowledge the World Health Organization for the technical support and guidance offered for developing this work.​​​​

​

ADRs              -           Adverse Drug Reactions

AEFI               -           Adverse Events Following Immunization

AESI               -           Adverse Event of Special Interest

AVSS              -           Active Vaccine Safety Surveillance

BCG                -           Bacillus Calmette-Guerin

CSF                 -           Cerebrospinal fluid

DT                   -           Diphtheria Tetanus

DTaP               -           Diphtheria Tetanus Acellular Pertussis vaccine

DTwP              -           Diphtheria Tetanus Whole Cell Pertussis vaccine

DTPa-HepB-Hib -    Diphtheria Tetanus Acellular Pertussis, Hepatitis B and

EPI                  -           Expanded Programme on Immunization

GVAP             -           Global Vaccine Action Plan

Hep B              -           Hepatitis B Vaccine

Hib                  -           Haemophilus influenza type b vaccine

IPV                 -           Inactivated Polio Vaccine

NIP                 -           National Immunization Programme

OPV                -           Oral Polio Vaccine

MMR              -           Measles Mumps Rubella

MOH               -           Ministry of Health

NITAG           -           National Immunization Technical Advisory Group

OPV                -           Oral Polio Vaccine

SIO                 -           State Immunization Officer

VAPP              -           Vaccine Associated Paralytic Poliomyelitis

VPD                -         Vaccine Preventable Disease

WHO              -           World Health Organization

SFDA              -           Saudi Food and Drug Authority

​Vaccines are biological substances that are administered to individuals to elicit immunity (protection) against specific diseases. Such products are formulated together with adjuvants and/or excipients, and like all medical products, may cause adverse events following their administration to some individuals. Despite the fact that such adverse events following immunization (AEFIs) are mostly mild and very rarely severe, measures still need to be put in place to monitor and prevent their occurrence and take appropriate regulatory action(s) on the products themselves if needed.

A good vaccine is one that provides the best protection and gives rise to minimum adverse events. AEFIs can arise through a variety of reasons: these include events that could be inherent to the vaccine product, or related to the quality, or immunization error or immunization anxiety or could be coincidental. A robust AEFI surveillance system in a country will help authorities to detect, manage and prevent AEFIs.

In Saudi Arabia, the Ministry of Health (MOH) operates the Expanded Programme on Immunization (EPI) through the National Immunization program (NIP) department. NIP is responsible for setting up policy guidelines and standards for selection, supply and utilization of vaccines in the country. NIP has done a tremendous job and some of the notable achievements of the programme include achieving immunization coverage of over 95 % for all primary immunization, establishing a cold chain system, engaging state and district authorities in monitoring vaccine use, training and developing healthcare providers as well as establishing linkages and networking with international stakeholders.

Likewise, the National Regulatory Authorities - NRAs (Saudi Food and Drugs Authority –SFDA) monitor the safety of all medical products including vaccines. The SFDA uses spontaneous pharmacovigilance system to collect any suspected adverse drug reactions experienced by patients. The SFDA is also responsible for authorization of marketing all medicines including vaccines. All vaccine manufacturers are required by law to register their products before supplying and distributing them in the country.

Reporting of AEFI and subsequent investigation may trigger regulatory action including withdrawing the marketing authorization of a vaccine, instructing vaccine manufacturers to change their product labels, restricting the use of vaccines to specific patient groups or recalling defective vaccine batches from the market.

The overall goal is the protection of the health and wellbeing of the entire population particularly infants, children and pregnant women and the general population who depend on vaccines to protect them from serious vaccine preventable diseases (VPD). This manual outlines the processes and procedures to be followed by healthcare providers in reporting, documenting and preventing AEFIs, as well as the roles and responsibilities of stakeholders responsible for the planning and delivery of immunization programs in Saudi Arabia in close partnership. The manual also outlines the surveillance system and provide tools and procedures needed to report and manage AEFIs. An understanding of the types of AEFIs, investigation techniques, specimen collection, managing AEFIs and communication including communicating with the media, are also described in this document.

It is anticipated that healthcare providers will read and use this manual and thus appropriately manage, report, and prevent AEFIs in the country. The manual will also bring together stakeholders and allow for networking and improved collaboration in the process of detecting, analysing and preventing AEFIs. 

A brief introduction to causality assessment has been provided in this manual. Advanced readers are encouraged to access the WHO website:

https://www.who.int/publications/i/item/9789241516990 for more information.​

A vaccine is a biological product that produces and enhances immunity to the particular VPD for which it is targeted. A vaccine contains the disease-causing microorganism or virus, or a portion of it, in a form that is incapable of causing the actual disease.  It is usually made from either live attenuated or inactivated (killed) forms of the microbe, or from its toxin or one of its surface proteins.

2.1.1 Primary components of vaccines

Vaccines may be monovalent or multivalent (polyvalent). A monovalent vaccine contains a single strain of a single antigen/immunogen (e.g. measles vaccine), whereas a polyvalent vaccine contains two or more strains/serotypes of the same antigen/immunogen (e.g. t OPV and IPV each of which contain three attenuated polio virus types).

Combination (or combined) vaccines contain two or more different antigens (e.g. DTwP, DTPa-HepB-Hib). The potential advantages of combination vaccines include reduction in the cost and difficulty of shipping and storing and administering multiple vaccines, avoiding multiple injections, reducing the cost of extra health-care visits, improving timeliness of vaccination, and facilitating the addition of new vaccines into immunization programmes.

There is no evidence that the administration of several antigens in combined vaccines increases the burden on the immune system, which is capable of responding to millions of antigens at a time. Combining antigens usually does not increase the risk of adverse reactions and can lead to an overall reduction in adverse reactions.  For instance, it can decrease the number of anxiety-related reactions and the chances of immunization error-related reactions.

2.1.2 Other components of vaccines

In addition to the primary antigen(s), vaccines contain small quantities of other substances. Sometimes AEFI can result from one of the other substances. They include,

Adjuvants: Substances added to a vaccine to enhance the immune response, thus making it possible, in some cases, to reduce the amount of antigen (immunogen) per dose or the total number of doses needed to achieve immunity.

Antibiotics: Antibiotics are used during the manufacturing phase to prevent bacterial contamination of the tissue culture cells in which the viruses are grown.

Preservatives: These are chemicals (e.g. thiomersal, phenol derivatives) that are added to killed or subunit vaccines in order to inactivate viruses, detoxify bacterial toxins, and remain in the vial to prevent serious secondary infections in multidose vials as a result of bacterial or fungal contamination after they are opened. 

Stabilizers: Stabilizers are used to help the vaccine maintain its effectiveness during storage.

2.1.3 Classification of vaccines

As alluded to above, there are four types of vaccines: live attenuated, inactivated (killed antigen), subunit (purified antigen) and toxoids (inactivated toxic compounds). The characteristics of these vaccines differ, and the characteristics determine how the vaccine works.

Table 2.1. Classification of vaccines

2.1.4 Contraindications and precautions to vaccination

A contraindication to vaccination is a rare characteristic in a recipient that increases the risk of a serious adverse reaction if the vaccine is given. Ignoring contraindications can lead to avoidable vaccine reactions. One of the most serious reactions following vaccination is anaphylaxis which is the only contraindication applicable to subsequent doses of the same vaccine. Most contraindications such as severe acute illnesses (e.g. acute respiratory tract infection) or treatment with steroids are temporary and the vaccination can be administered later. These are called temporary or relative contraindications.

Precautions, in contrast, are events or conditions that should be considered in determining if the benefits of the vaccine outweigh the risks (especially if the would-be recipient is immunocompromised or pregnant). Precautions stated in the product labelling may sometimes be inappropriately interpreted as contraindications, resulting in missed opportunities to vaccinate.​

​An adverse event following immunization is any untoward medical occurrence (unfavourable or unintended sign, abnormal laboratory finding, symptom or disease) which follows immunization and which does not necessarily have a causal relationship with the usage of the vaccine. Reported adverse events can either be true adverse events - i.e. resulting from the vaccine or immunization process - or coincidental events that are not due to the vaccine or immunization process but are temporally associated with immunization. The five categories of AEFI as defined by CIOMS and WHO are described in table 2.1

Table 2.1 Cause-specific categorization of AEFI (CIOMS/WHO 2012)

2.2.1 Vaccine reactions

Based specifically on cause, seriousness and frequency, vaccine reactions may be grouped into two broad categories:

A. Cause-specific vaccine reactions: 

• vaccine product-related reaction and

• vaccine quality defect-related reaction

B. Vaccine reactions by seriousness and frequency:

• common or minor reactions; 

• rare or serious reactions.

A. Cause-specific vaccine reactions 

Vaccine product-related reaction: This is an individual’s reaction to the inherent properties of the vaccine, even when the vaccine has been prepared, handled and administered correctly. Most often the exact mechanism of a vaccine product-related reaction is poorly understood. The reaction may be due to an idiosyncratic immune mediate reaction (e.g. anaphylaxis) or to replication of the vaccine-associated microbial agent (e.g. vaccine-associated poliomyelitis following OPV which contains attenuated live virus). 

Vaccine quality defect-related reaction: This is a due to a defect in a vaccine (or its administration device) that occurred during the manufacturing process. Such a defect may have an impact on an individual’s response and thus increase the risk of adverse vaccine reactions. Insufficient inactivation of wild-type vaccine agent (e.g. wild polio virus) during the manufacturing process or contamination introduced during the manufacturing process could cause the vaccine quality defect-related reactions. 

B. Vaccine reactions by seriousness and frequency 

Most vaccine reactions are minor and subside on their own. Serious reactions are very rare and, in general, do not result in death or long-term disability. Table 2.2 describes the frequency of occurrence of reported adverse events.

Table 2.2 Frequency of occurrence of reported adverse reactions 

Notes

1. Reactions (except anaphylaxis) do not occur if already immune (~90% of those receiving a second dose are immune): children over six years unlikely to have febrile seizures 

2. VAPP Risk is higher following the first dose (1 in 750,000 compared to 1 in 5.1 million for subsequent doses) and for adults and immunocompromised.

3. Seizures are mostly febrile and the risk depends on age, with much lower risk in infants under the age of 4 months. 

Immunization error-related reactions

The term “Immunization" as used here means the “use" of a vaccine for the purpose of immunizing individuals. “Use" includes all processes that occur after a vaccine product has left the manufacturing/packaging site – i.e. handling, prescribing and administration of the vaccine.

Immunization error-related reactions are usually preventable and they divert attention from the benefit of the immunization programme. Some of them are described in Table 2.5. The identification and correction of these errors in a timely manner are, therefore, of great importance.

Table 2.5 Immunization error-related reactions

 

​An immunization error-related reaction may sometimes lead to a cluster of events associated with immunization. These clusters are usually linked to a particular provider or health facility, or even to single or multiple vials of vaccine that have been contaminated or inappropriately prepared. For instance, freezing vaccine during transport may lead to an increase in local reactions. The details of an approach to investigating AEFI clusters are described later.

Immunization stress related response (ISRR) formerly known as immunization anxiety related reactions

The term “immunization anxiety-related reaction" was previously used to describe a range of symptoms and signs that may arise around immunization that are related to “anxiety" and not to the vaccine product, a defect in the quality of the vaccine or an error of the immunization programme. These reactions are described as AEFI arising from anxiety about immunization and include vasovagal-mediated reactions (eg fainting), hyperventilation-mediated reactions and stress-related psychiatric reactions or disorders.

The term “anxiety" does not, however, adequately cover the presentation of all these AEFI and anxiety may not manifest during such events. The term ISRR is used to cover the entire spectrum of manifestations (symptoms and signs) of a stress response rather than a single symptom, anxiety. Individual responses to stress vary from person to person or may change according to time or context. In this cause-specific definition, stress results from the process of immunization. As for other AEFI, symptoms may occur during or after immunization; however, in contrast to other AEFI, the symptoms of an ISRR may also occur immediately before immunization.

When ISRR occur in a cluster, they may generate public concern, and, if they are linked to immunization, they may halt or undermine the immunization programme. Although the vaccine is not the underlying cause, the event may be wrongly attributed to it. Halting an immunization programme in such situations will give the impression that the vaccine or the programme is the cause. Various terms have been used to describe such “outbreaks", including “mass hysteria", “epidemic hysteria" and “mass psychogenic illness" ISRR may spread by direct contact and via social media.

​Coincidental events

An event may occur coincidentally with immunization and sometimes be falsely attributed to the vaccine i.e. a chance temporal association is falsely attributed to immunization. Such temporal associations are inevitable especially in a mass immunization campaign.

Vaccines are normally administered early in life when infections and other illnesses are common, including manifestations of underlying congenital or neurological conditions. It is, therefore, possible to encounter many events, including deaths that can be falsely attributed to vaccine through a chance association.

For example, incidence of sudden infant death syndrome (SIDS or “cot death") peaks around the age of early childhood immunization. Consequently, many SIDS cases will occur in children who have recently been immunized. However, several well designed studies have shown that the association of SIDS and immunization is coincidental and not causal.

Coincidental adverse events may be predictable. The number of events to be expected depends upon the size of the population and the incidence of disease or death in the community. Knowledge of these background rates of disease and deaths, particularly age-specific disease incidence rates, allows estimation of the expected numbers of coincidental events.

A calculation is shown in Table 2.6 relating to the incidence of infant (under one year) deaths in selected countries to the number of deaths temporally associated with routine DTP or pentavalent vaccine (PVV) immunization. As shown, infant mortality rates result in coincidental deaths in the day, week and month after immunization which are only temporally related to immunization. The actual number of coincidental deaths depends on the population size and infant mortality rate.

​Table 2.6 Estimated numbers of coincidental infant deaths that could be temporally linked to immunization (for example with DPT/PVV) in the month, week and day after immunization in some selected countries 

*http://www.stats.gov.sa/en/indicators/55

- General Authority for Statistics –Kingdom of Saudi Arabia

2.2.2 Key AEFI terminology

Cluster of AEFI

A cluster is defined as two or more cases of the same or similar event, which is related in time and has occurred within the same district or geographical unit or associated with the same vaccine, same batch number administered or same vaccinator.

Signal

Information that arises from one or multiple sources which suggests a new potentially causal association or a new aspect of a known association, between an intervention and an event or set of related events, either adverse or beneficial, that is judged to be of sufficient likelihood to justify verificatory action.

Adverse Event of Special Interest (AESI)

An adverse event of special interest (serious or non-serious) is one of scientific and medical concern specific to a particular product or programme, for which ongoing monitoring and rapid communication to the relevant authority (eg regulators) is needed. Such an event may require further investigation in order to characterize and understand it.

An AESI is a pre-specified medically significant event that has the potential to be causally associated with a vaccine product that needs to be carefully monitored and confirmed by further special studies.​

Vaccines are very rarely contraindicated. However, it is important to check for contraindications to avoid serious reactions. For example, a vaccine is contraindicated if there is a history of anaphylaxis to a given vaccine or its components in previous vaccinations. 

Vaccine anaphylaxis is very rare. However, it is recommended that preparedness to provide emergency treatment for anaphylaxis is necessary in all clinic settings. All immunization providers need to be trained and develop competence in recognizing and managing anaphylaxis and have epinephrine (adrenaline) available. 

For parents, advice should be given on managing the common minor reactions, in addition to instructions on seeking proper medical care if there are more severe symptoms. Such action will help to reassure parents about immunization and prepare them for common reactions.

Antipyretic drugs, in a recommended dosage and schedule, can be given as recommended by the prescriber (or manufacturer). For an example, paracetamol, at a dose of up to 15 mg per kg every 68 hours with a maximum of four doses in 24 hours, is useful for common minor reactions; it eases pain and reduces fever. However, it is important to advice against overuse of paracetamol or any other antipyretic drug as overdosing may harm the vaccinee. A febrile child can be cooled with a tepid sponging or bath, and by wearing light cool clothing. Extra fluids need to be given to children with fever. For a local reaction, a cold cloth applied to the site may ease the pain.

Using local remedies for any serious vaccine reaction can risk the health and life of the vaccinee and is strongly discouraged. Early medical care by a qualified clinician will minimize any unwanted outcome and ensure early recovery, and may also save lives.​

​As mentioned in the previous chapter, immunization error-related reactions are preventable and identification and correction of these errors in a timely manner are important.

Prior to the introduction of auto-disable (AD) syringes, the most common immunization error was an infection as a result of a non-sterile injection because of contamination of the vaccine or diluent vial or the injecting device (syringe and/or needle). The infection could manifest as a local reaction (e.g. suppuration, abscess) or a severe systemic reaction (e.g. sepsis, toxic shock syndrome). In addition, there was the perception of a risk linking immunization with blood borne infections. Nevertheless, one needs to consider infection that can occur in cases of mass vaccination or in disaster situations, particularly if there is a shortage of supplies or problems with logistics. This can be avoided by proper planning and preparedness of programme managers.

The symptoms arising from an immunization error may help to identify the likely cause. For instance, children immunized with contaminated vaccine (usually the bacterium Staphylococcus aureus) become sick within a few hours with an injection site reaction (local tenderness, redness and swelling) and then develop systemic symptoms (vomiting, diarrhoea, high temperature, rigors and circulatory collapse). Bacteriological examination of the vial, if still available, can confirm the source and type of infection.

Sterile abscesses, while rare (~1 per 100 000 doses) are local reactions from aluminium-containing vaccines, especially DTP. They, along with other local reactions, are more likely to occur if there is inadequate shaking of the vaccine before use, superficial injection and use of vaccine that had been frozen. Contamination of vaccine or injection equipment can lead to a bacterial abscess. For BCG vaccine, injection abscess can result from improper technique of injection (subcutaneous rather than intradermal injection).

Ignoring contraindications may lead to serious vaccine reactions and is considered an immunization error. The immunization team should be clearly aware of such contraindications and any precautions. Any uncertainty should be referred to a higher level – a programme manager, paediatrician or physician. However, it is equally important not to overreact to concerns of false contraindications as this may lead to missed opportunities for vaccination, reducing coverage and thereby increasing the risk of disease in both individuals and the community.

Health-care workers also need a clear understanding of contraindications and precautions. As mentioned in the previous chapter, precautions are not contraindications, but a decision on whether to vaccinate requires a case-based assessment where the risk of the vaccine is balanced against the potential benefits. The use of live vaccines in pregnancy is a good example of this. 

To avoid/minimize immunization error, the following should be observed.

• It is both important and necessary to maintain the cold chain at all levels.

• Vaccines must be reconstituted only with the diluents supplied by the manufacturer.

• Reconstituted vaccine should be maintained in the recommended cold chain and used within six hours after reconstitution; it must be discarded at the end of each immunization session and should never be retained.

• Other than vaccines, no other drugs or substances should be stored in the refrigerator of the immunization centre.

• Immunization workers must be adequately trained and closely supervised to ensure that proper procedures are followed.

• Careful epidemiological investigation of an AEFI is needed to pinpoint the cause and to correct immunization practices.

• Prior to immunization, adequate attention must be given to contraindications.

Follow-up and corrective actions following immunization error-related reactions should be based on the findings of the investigation. Depending on the nature of the immunization error, these actions can be both general (e.g. training and awareness) and specific (e.g. strengthening cold chain maintenance if the problem found to be related to cold chain issues). Continued monitoring and supportive supervision can help to minimize these adverse events.

The immunization environment is important to prevent ISRR. When possible, vaccines should be administered in a calm, private, planned environment. This may be difficult when vaccines are provided during a short period for large groups of individuals, such as in mass campaigns or a school programme

A rapid, targeted history before immunization can help to identify individuals with predisposing risk factors for an ISRR. The risk factors relevant to immunization include:

• age 10–19 years (but can occur outside this age group)

• history of vasovagal syncope

• a previous negative experience (e.g., from pain or vasovagal syncope) and an expressed fear of injections, including blood–injection–injury phobia and

• pre-existing conditions such as anxiety disorders and developmental disorders (particularly autism spectrum disorder).

If the responses to these questions suggest very strong needle fear (without avoidance), consideration should be given to treating the fear before future immunizations or at least taking time to manage the special needs of these individuals. If the fear leads to refusal (i.e., avoidance), additional measures may be required before immunization, such as counselling or behavioural interventions with appropriate health professionals. In selected circumstances of extreme fear and when the expertise is available, a patient might be referred for pharmacological anxiolytics and sedation. In some very rare instances, immunization could be done concurrently with a procedure that requires anaesthesia.

Further details are available in the Immunization Stress-Related Responses, A manual for program managers and health professionals to prevent, identify and respond to stress-related responses following immunization .[1]​

[1] https://www.who.int/publications/i/item/9789241515948 ​

Every health facility providing vaccinations should have health staff trained in the practical steps for recognition and treatment of anaphylaxis. They should have immediate access to an emergency kit containing adrenaline. Once anaphylaxis is suspected consider the vaccine recipient as having a potentially life-threatening condition and begin treatment immediately and follow the treatment protocol below.

Table 2.7 Differentiation of anaphylaxis from an acute stress response of general and vasovagal reaction with syncope
​

1. First aid response which includes;

• Stop administering any further vaccine.

• Call for help and never leave the vaccine recipient alone.

• Place the vaccine recipient in the supine position (lying down flat on the back with head lower than the legs if patient is hypotensive). If the vaccine recipient has difficulty breathing, place him/her in a semi-supine (lying flat on the back but with bent knees/elevated legs) position. Do not stand the vaccine recipient up or allow the vaccine recipient to walk. If already unconscious, place the vaccine recipient in the recovery position (on the left side) and ensure that airway is clear.

• Assess airway, breathing and circulation (ABC). If appropriate, begin cardiopulmonary resuscitation (CPR).

2. Diagnose anaphylaxis by doing a RAPD assessment by examining for symptoms and signs involving the following body systems;

• Rash and mucosa

• Airway and respiratory

• Pulse and cardiovascular

• Diarrhoea and gastrointestinal

• Administer initial treatment – the first dose of Adrenaline

• Draw up the correct dose of adrenaline 1:1000, according to age and/or weight.

• Generally, the dose for individuals weighing more than 50 kg is 0.5 ml.

• Using the appropriate needle size (length and gauge), administer adrenaline by deep intramuscular injection into the opposite limb to that in which the vaccine was given. For children, administer in the upper lateral thigh, and in adults in the upper arm (deltoid) or into the muscle of the upper lateral thigh.

• Give oxygen by face mask (oral-nasal mask), if available.

3. Assess response and treat if ongoing respiratory and/or cardiovascular symptoms or signs

• If needed, repeat same dose of adrenaline IM every 5-10 minutes up to TWO additional doses, give high flow oxygen, if available

4. Documentation and patient transfer

• Call an ambulance (or arrange other means of transport) after the first injection of adrenaline, or sooner if there are sufficient people available to help you.

• Record (or get someone to record), vital signs (pulse rate, respiratory rate and blood pressure) all other symptoms and signs, as well as time and exact dose of any medication given. Make sure the details accompany the vaccine recipient when s/he is transferred to the appropriate care centre.

5. Further management is usually provided in a medical centre /hospital

• If shock (hypotension) IV Saline

• If extrathoracic airway obstruction (stridor) – Nebulised adrenaline/airway intervention

• If intrathoracic airway obstruction (wheeze) Nebulised salbutamol and airway intervention

Table AEFI Treatment Kit​

​

​Surveillance for adverse events following immunization (AEFI) is an integral part of the National Immunization Program (NIP), and reinforces the safe use of all vaccines in the country while also helping to maintain public confidence in its immunization program. As shown in fig 4.1, this is done systematically. 

 The objectives of AEFI surveillance are to:

• Rapidly detect and respond on time to the occurrence of an AEFI

• Identify, correct and prevent immunization error related reactions. 

• Facilitate AEFI causality assessment. 

• Recognize clustering or unusually high rates of AEFI, including those that are mild and/or “expected”.

• Identify potential safety signals (including previously unknown vaccine reactions), and generate hypotheses that may require further investigation.

• Generate information with which to effectively communicate with parents, the community, media and other stake holders, regarding the safety of vaccines used in Saudi Arabia. 

Vaccine recipients themselves and/ or parents of immunized infants/children, health care providers at immunization facilities and staff in immunization facilities are most likely to recognize or detect AEFIs when they first occur. Any AEFI case that is therefore notified to any health care provider working within the health care system, should be reported to the AEFI coordinator using the standard reporting form (Annex 1) through the fastest means possible.  The AEFI COORDINATOR should in fact be informed of any Serious AEFI cases by telephone and this should be followed up by completion and submission of the reporting form.

The reportable AEFI include serious AEFI, AEFI as a result of potential immunization errors, clusters, AEFI causing parental or community concern, those that are unexpected, and any that are known but occur with unexpected frequency. Table 4.1 below provides case definitions of commonly reportable AEFI. However it needs to be stressed that health workers should report all cases that are notified to them. 

Table 4.1 Case definitions of the reportable adverse events.

​​​

​All vaccination staff must be able to recognize AEFIs and report them. However, accurate diagnosis of AEFIs requires staff training and education. Health care providers also have the additional responsibility to manage AEFI and, if necessary, refer such patients for any required treatment.​

Traditionally AEFI reports in Saudi Arabia are collected in paper-based formats. However, newer platform is introduced for reporting that is a mobile-friendly website. Saudi Arabia has developed the Saudi vigilance system for AEFI reporting. The system is able to generate excel data outputs. For AEFI reporting, the critical data elements in the AEFI reporting form are captured by Health care providers at subnational level. The data are then transferred to a database that is accessed at the district, province and national level in the country. The NIP and the SFDA review the data to identify if there are “patterns" that are suggestive of signals and appropriate action is taken. After the data is reviewed at national level, the same is encrypted and shared with the WHO global database of individual case safety reports (ICSRs).​​

Subnational Stakeholders

In Saudi Arabia, the subnational stakeholders in AEFI reporting and investigation are

1. Parents/ guardian

2. Health workers 

National stakeholders in AEFI investigation

In Saudi Arabia, the national stakeholders are

1. Saudi Arabia NIP and Saudi Food and Drugs Authority (SFDA)

2. National AEFI committee​

The ultimate goal of an AEFI field investigation is to find the cause of the reported AEFI(s) and prevent recurrence. Remedial action needs to be taken promptly for immunization error related AEFI. Even if the cause cannot be identified or the cause of the event was due to some other reason, the fact that staff had investigated the incident itself will increase public confidence in the immunization program. 

The purpose of investigating AEFI cases are:

• To confirm the reported diagnosis and/or propose other possible diagnoses as well as clarify the outcome of the medical incident comprising the AEFI. 

• To ascertain the particulars, circumstances and procedures around the vaccine used to immunize the affected recipient. Most importantly, identify any potential vaccine related link to the given AEFI.

• To examine the operational aspects of the programme. Even if an event seems to be vaccine product induced or coincidental. 

• To determine whether a reported event was a single incident or one of a cluster and if it is a cluster, confirm that the suspected immunizations were indeed given and the individual vaccines that were used.

• To determine whether unimmunized people are experiencing the same medical incidents.

IMPORTANT: The flowchart below – describing the routing, timeline and action taken for AEFI reporting in SA

​

4.4.1 Role of the Subnational stakeholders

Role of the parent/ guardian

At the time of immunization, it is important for health workers to sensitise the parents about expected events such as fever and pain at injection site etc. following immunization. Parents should be advised about simple home remedies (e.g. correct positioning of the child when sleeping, increasing intake of fluids, sponging, breast feeding, antipyretics etc.) should such events occur; however, at the same time, they should also be instructed to report severe expected events (e.g. very high fever, not responding to anti pyretic) or other unusual events to the health worker if they occur. 

Role of the health worker

If home remedies do not work, vaccine recipients themselves and/ or parents or guardians of immunized infants/children usually report the event to health care providers at immunization or other health care facilities. Sometimes staff in these facilities recognize or detect AEFIs when they first occur. All such AEFI cases brought to the notice of the health care worker or detected by the worker should be reported to the AEFI coordinator using the standard reporting form (Annex 1).

Thus the main role of the health worker is to provide primary medical care and report the basic details about the notified adverse event  to the district by completing the AEFI reporting form (preceded if appropriate with a preliminary report by telephone if it is a serious event).

Role of stakeholders at the district and the state level

When an AEFI report (Annex 1) is received by the AEFI COORDINATOR , he should review the report and determine if the reported AEFI case meets the criteria required for a detailed investigation. If necessary he should contact the primary reporter and visit the locality of the event and interview relevant stakeholders for additional information. The case may be considered 

1. Not warranting detailed investigation if it is a minor AEFI and NOT serious AEFI, he should indicate this on the reporting form and email/ fax the same to the SFDA and the MOH levels to the following

a. NIP  manager : Dr. Musallam Abohasan : Abohasan-m@moh.gov.sa

AEFI program supervisor : Dr. Rawan Melibary Rmelibary@moh.gov.sa

b. NRA level to the following :

 NPC: npc.drug@sfda.gov.sa​ 

2. Warranting a detailed investigation if it is a Serious AEFI (death, hospitalization, significant disability, life threatening, or congenital anomaly/ birth defect)

or is a part of a cluster, or a part of a group of events above expected rate/ severity,

or a suspected signal, He should discuss the same with the local experts (or technical expert committee if available) and plan for a detailed field investigation. Prior to initiating an investigation, he should e-mail the report (Annex 1) to the section level and national levels as described above​

If the AEFI COORDINATOR and the experts feel that the investigation can be done locally, they can visit admitted patients, Health affairs and initiate the detailed investigation along with appropriate members of the local health care team. If however assistance is required for investigation from the state or national level, the NIP and NRA should be contacted and assistance for an investigation solicited. National investigations should be led by a team from the national AEFI committee, supported by the NIP in Saudi Arabia and the SFDA. During field investigations, the AEFI investigation form (Annex 3) should be used as a guide to collect suitable information.

The investigators should seek to document any deficiencies found in a generic way and suggest corrective measures, and not single out any individuals to blame. While an individual may have been at fault, it is more effective to focus on identifying the problems in the system and procedures leading to the event. This is more effective in avoiding similar errors in the future, than blaming or punishing individuals. Such an approach is essential to ensure that AEFI reporting is encouraged for the ultimate benefit of all patients and the immunization program as a whole. It is also much more likely to improve system performance. Errors provide opportunity for learning and creating a system that encourages continued improvement. Hiding errors will only serve to form the basis for more errors.

The specific activities conducted at this point will include the following

• • Confirm the AEFI, assign a unique report identifying number, complete ALL details  in the AEFI reporting form (in case any of them were missing when reporting) and initiate AEFI investigation.

  • Convene a local experts (or technical expert committee if available) planning meeting prior to the investigation.

  • With the experts, the AEFI COORDINATOR  should visit as required the patient, the care provider(s) and the hospital; interview relevant stakeholders (parents, health worker, treating doctor, vaccine supply focal person); and conduct the investigation of the AEFI case.

  • Complete the AEFI investigation form (Annex 3).

  • Initiate collection of medical reports, a post-mortem report (if available), vaccine vials (if necessary, and kept under cold chain conditions), logistic samples, and laboratory reports e.g. CSF, Serum (or other biological products).​
  

  
   
  

Generally before the AEFI is attributed to any vaccine product related problems, the investigator should rule out any potential immunization errors and obvious coincidental events, as these are more common. Therefore, the investigation should first try to rule out immunization errors related to the storage, handling, reconstitution or administration of vaccines.

Attention can then focus on other events. Details of coincidental events can be determined by reviewing hospital admissions for similar conditions during the same period and verifying their vaccination status. A quick review of the morbidity pattern of similar conditions in the previous years can also indicate if the event is a part of a similar pattern observed in the previous years.  The medical literature can also help, as the estimated background incidence of various conditions may be available in the published domain.

Once the investigation is initiated, the District / State investigator should inform the NIP Saudi Arabia and the SFDA on the status and progress of the investigation. This is necessary, as a national level officer should be the spokesperson of the government to the media and the public about the investigation.  The completed case investigation form (annex 3) along with the supporting documents such as the medical report, vaccine, logistic samples, laboratory reports e.g. CSF, Serum (or other biological products) should be sent to the NIP/ SFDA within 7 days of initial case notification. If this is not possible, at least a progress report should be made with details on when the completed report can be expected.

It is important to remember that in case state or national assistance for an investigation is requested, more accurate information can be obtained by a single coordinated investigation rather than a piecemeal investigation. Table 4.2 summarises the key steps in an AEFI investigation.

Investigator(s) may use the “WHO Aide Memoire on AEFI Investigation" as a guide. This is available at www.who.int.immunization_safety/en

Table 4.2 Steps in an AEFI investigation 

Role of the National stakeholders

When the national AEFI focal point of the NIP Saudi Arabia receives the AEFI reporting form, it is essential to review it in the context of other reported AEFI received from all parts of the country, particularly in the same period of time, to see if this report may constitute a signal. This can be done by appending data into a national AEFI linelist with information from the reporting form and reviewing the data or running analyses as needed. If similar cases were reported earlier, it is essential to determine if an epidemiological linkage or other pattern can be identified if there is one. The need for technical or operational assistance for the investigation has to be assessed. Expert advice can be sought from the National AEFI Committee at this point.

The SFDA and the National AEFI Committee play a key role in supporting the immunization program for AEFI investigation and causality assessment. They also provide recommendations to the Saudi Arabia National Immunization Technical Advisory Group (NITAG), the MOH and EPI on vaccines based on their causality assessment findings. The SFDA and the NIP Saudi Arabia together constitute the National AEFI secretariat and together they coordinate and provide technical/logistical support to conduct the meetings of the National AEFI Committee (Fig 4.2).

NIP is responsible for providing all feedback to the relevant stakeholders at the state and district level within 7 days of causality assessment or potential signals determined by data review/analysis at the national level. They are also responsible on following up on the actions recommended at the national level and state level (e.g. change in logistics, cold chain, training after program errors etc.) and ensuring that they are implemented.

The SFDA or the national pharmacovigilance centre is responsible to share the information with the global community by uploading the information into the Global pharmacovigilance database – VigiBase^®, maintained by the Uppsala Monitoring Centre under the WHO International Drug Monitoring Program – using information available in the completed case investigation form (annex 3). A copy of the uploaded case details in VigiBase^® should be provided to NIP Saudi Arabia on a monthly basis. The SFDA can also provide information on the vaccines and lots distributed in the country when requested by the AEFI committee, NIP Saudi Arabia and the Saudi Arabia National Immunization Technical Advisory Group (NITAG). The SFDA can also provide additional information on AEFI from other sources. ​

In the event of an identified death following immunization, the field investigation has to be initiated immediately.  Within 24 hours the death should be notified to all administrative levels concerned, including the District and State immunization officers, the NIP Saudi Arabia and the SFDA. Investigation of the case should be carried out by a team of experts from relevant areas, including clinicians. As a death causally linked to immunization is extremely rare (anaphylactic reactions being one of the only 2-3 known events), major programmatic errors may be involved and thus an investigation to rule those out has to be conducted without any delay to prevent additional cases.  As any fatality temporally linked to a vaccination can cause panic, the public will also demand an immediate explanation. 

A post mortem is preferred and recommended following all deaths suspected to be caused by a vaccine / immunization. However, the decision to conduct a postmortem should be within the religious, cultural acceptance and legal framework of the local population. ​​

A cluster of AEFI is defined as two or more cases of the same adverse event related in time, place or vaccine administration. Apart from checking on these three factors, the investigator should look for AEFI occurring in similar age groups and populations with genetic predisposition or disease.

Cluster investigation begins by establishing a case definition for the AEFI and related circumstances and by identifying all cases that meet the case definition. The investigator should   demarcate the cluster and identify common exposure factors within the cluster

Cluster identification (i.e. cases with common characteristics) is done by gathering details (when and where) of vaccines administered. This can be achieved by collecting and recording

• Detailed data on each patient;

• Programme-related data (storage and handling, etc.); and

• Immunization practices and the relevant health workers’ practices.

Common exposures among the cases can be identified by reviewing:

• All data on vaccine(s) used (name, lot number, etc.); 

• Data on other people in the area (also non-exposed); and 

• Any potentially coincident factors in the community.

When an AEFI cluster has been identified, the cause-specific definitions provide a framework for investigation and causality assessment. Usually the key considerations will be to investigate the possibility of an immunization error vaccine or a quality defect. The possibility of immunization error must be considered when events cluster in one setting without a similar change in frequency in other settings using the same vaccine. On the other hand, if an increased frequency of events is reported from multiple settings the possibility of a quality defect must be considered more strongly. Clusters of fainting after immunization are well-recognized immunization anxiety-related reactions during immunization programmes targeting adolescent girls.

Fig 4.3 Identifying cause of AEFI cluster

​

For relatively new vaccines or established vaccines used in new target populations, a cluster may represent a previously unrecognized vaccine product-related reaction. Knowledge of the background incidence of events which may occur in causal relationship with a vaccine is therefore essential for assessing a cluster in terms of the strength of the signal it may provide.

4.6.1 Interpretation of results from AEFI clusters

If all cases received vaccines from the same health worker/facility and there are no other cases, an immunization error is likely. If all cases received the same vaccine or lot, and there are no similar cases in the community, a problem with the vaccine or the respective lot is likely. If the event is a known vaccine reaction but is found to occur at an increased rate, an immunization error or a vaccine problem are likely causes. Finally, if cases in the unvaccinated population are occurring at about the same rate/proportion as among the vaccinated from the same area in the same age group, the adverse event was probably coincidental (Fig 4.3). ​​

In Saudi Arabia, passive surveillance systems collect information on AEFIs as described above are useful for the identification of potential safety signals for adverse events that were unknown at the time of vaccine authorization or that are unexpected. However, these passive systems have challenges to differentiate between a reaction following immunization from a coincidental event.

Saudi Arabia is developing systems for Active Vaccine Safety Surveillance (AVSS) that aims to collect complete, accurate information about adverse events following immunization (AEFIs) and their risk factors in a defined population via a continuous organized process. This information is collected with defined objectives which are to investigate one or more AEFIs that are pre-specified adverse events of special interest (AESI). AVSS, unlike passive surveillance systems, collect relevant data from all individuals within a well-defined population, thereby minimizing under-reporting. 

AVSS system is planned to be used for signal detection (like passive surveillance systems) but they can also be used to determine:

• The rate of an event, in a defined population.

• The relative risk of the event:

               o The chance of the event occurring in those who were vaccinated with the specific vaccine, compared with those who were not or those who received a comparator vaccine.

               o The change in the event occurring over time.

• The occurrence of events in both vaccinated and unvaccinated individuals in the defined population.​​

Laboratories have an important role in AEFI case diagnosis and case management. They also have a key role in testing the quality of the samples of vaccines and the logistics used. 

Laboratory tests for the purpose of AEFI case diagnosis and case management conducted on the patient (eg blood, urine, radiology, ECG etc) are based on the provisional case diagnosis and recommendations of the treating physician. These tests are considered “routine” and should be performed in clinical laboratories. The results of these tests are important to confirm the case diagnosis and arrive at the “valid diagnosis” for assessing causality as described in section 7.2. 

Laboratory testing of samples of vaccines and logistics are rarely necessary.  It is not mandatory following an AEFI, particularly if the cause is evident such as a coincidental event or a program error. However, laboratory testing of vaccines and logistics are at times required to confirm or rule out the suspected cause. 
In the context of AEFI, sometimes additional specific tests on the patient, vaccines and logistics as outlined below may also be necessary to confirm the cause. The testing of additional specimens includes: 

Human specimens

• Histopathology, body fluids etc. can be done at laboratories identified and approved by the MOH. 

• Autopsy specimens at approved and accredited government forensic laboratories as identified by MOH

Vaccines and logistics

• Vaccines and diluents for sterility and chemical composition. 

• Syringes and needles for sterility. 

Only the appropriate specimen in the correct quantity required for the investigation should be collected. Laboratory specimens should be stored and transported as recommended and accompanied by clear supporting documents, reasons for specimen collection and any additional information required by the investigators. In case laboratory investigation is required, AEFI laboratory request form (Annex 4) should be completed and sent with any specimen collected. 

• - Laboratory testing is not a routine requirement but may be a part of an investigation.

• - Laboratory testing is costly and is recommended only when it is necessary.

• - However, securing samples (vaccine vials, syringes, blood etc.) and storing them correctly is important because later investigation may require them.

• Therefore, proper storage and transport of suspected samples is recommended.​​
  

It is difficult to generalize what specimens will be required in a given situation as it will depend on the symptoms and signs of the patient and the clinical decisions made by the doctor in charge of the case. Table 5.1 gives a general outline of some of the specimens that could be collected. The list is not exhaustive. It is necessary to record the type date and time of collection of each and every sample collected. Documents of clinical investigations and medical records related to the incident will support correct lab investigations. It is advised to consult the treating clinician(s) to make a decision on samples to be tested.

For biochemical, histo-pathological and microbiological examination, specimens should be handled at the district hospital and forwarded to the nearest laboratory, where facilities are available to carry out requested laboratory testing. If facilities for essential laboratory testing are not available at intermediate level (State/District) institutions, sending samples to national laboratory or an accredited laboratory abroad need to be considered after discussing with NIP.

In case of death suspected to be due to an AEFI, an autopsy needs to be performed as soon as possible (within 72 hours) to avoid tissue lysis (for e.g. in the adrenal glands), which can alter diagnosis. Samples for both toxicology and pathological examination should be sent to the reference laboratories identified by NIP as early as possible to avoid loss of biological samples due to decomposition. It is essential to ensure that a detailed patient's history is included in the autopsy form and submitted to the autopsy team to help them look for any underlying pathologies. 

5.1.1 Guide to human specimen sample collection

The details of the type of AEFI, the tests to be performed, the specimens to be collected, the process of storage and shipment and the labs are outlined in Table 5.1

Table 5.1 Type of AEFI, the tests to be performed, the specimens to be collected, storage and shipment procedures and the labs conducting tests ​

Vaccines and logistics samples from the site and the distribution point(s) should be collected as soon as possible and kept in cold chain. They should be sent to the laboratory for testing only on the recommendation of the local experts.

Testing of vaccines and logistics should be requested on a clear suspicion and not as routine and never before the working hypothesis has been formulated (Table 5.2). Determining which samples to send for testing (if any) depends on the working hypothesis for the cause of the event(s). If the used vial of suspect vaccine is available, it should be separately labelled and sent along with unused vials of the same lot.

The AEFI COORDINATOR  will be responsible for the packaging, cold chain maintenance and shipment of samples in the correct temperature to the national laboratory at SFDA laboratory. ALL specimens sent to the lab should be accompanied by a laboratory request form (Annex 4).

The laboratory will process the specimens and send the laboratory results to National NIP Manager and SFDA Director General. Laboratories will also send a copy of the laboratory results to all persons with contact details (complete address with postal code, phone and fax numbers and email address) mentioned in the lab request form

​

Falsified vaccines 

It is important to have increased vigilance within the supply chains within Saudi Arabia and regions likely to be affected by falsified vaccines. Increased vigilance should include hospitals, clinics, health centres, wholesalers, distributors, pharmacies, and any other suppliers of medical products.

Some indicators that a vial is falsified and may have been illicitly refilled may include:

• vials have scratches or signs of tampering

• labels show signs of damage

• the metal cap is dented, scratched or broken

• rubber seals are scratched or punctured

• foreign materials/particles visible inside the vial

• visible signs that the expiry date has been changed or tampered with

• the expiry date does not match the authentic batch number

• the product is available for private sale outside of authorized immunization programmes.

All, vaccines and medical products, must be obtained from authorized/licensed suppliers and authorized immunization programmes. The products’ authenticity and physical condition should be carefully checked. 

If the vaccinator suspects a falsified vaccine, it is important not to use them. It is important to seek advice from a healthcare professional or supervisor in case of doubt. If these vaccines were used, or an adverse reaction/event occurred after having used these vaccines, it is important to seek immediate medical advice from a qualified healthcare professional and to report the incident to the National EPI program and National Regulatory Authorities / National Pharmacovigilance Centre and report the same using the standard AEFI reporting form and investigations and testing are carried out by the authorities.

National regulatory / health authorities should immediately notify WHO of these falsified vaccines at rapidalert@who.int. ​​

Information on vaccine safety and the possible occurrence of AEFIs can be obtained from clinical examinations, interviews of health workers, parents and community leaders, review of registers (ANC, OPD and Immunization), Vaccine and Injection logbooks, observation of immunization administration, vaccine handling and storage and laboratory reports. Analysis of data on AEFIs consists of reviewing data from the following sources

• Data collated into a linelist

• Case investigation forms for each reported AEFI case, 

• Laboratory information (Human and vaccine related)

• Records about similar events in the community 

• Records of the implicated vaccine ​​

It is essential that all notified cases are reported (serious and non-serious AEFI) using the AEFI reporting form (Annex 1). All reported AEFI cases should be linelisted at all levels using the AEFI linelist (Annex 2). This is the first step of data management. Before the analysis, verify and reassure the data for accuracy. In addition to basic time, place and person analysis that should be done by the district and state program managers, other key analysis related to the performance of the surveillance system, include

• Timeliness and completeness of receiving AEFI forms.

• Identifying health institutions where AEFIs are not reported by checking on “zero reporting” or “nil reporting”. Determine whether it is due to failure of reporting or whether there are no AEFIs to be reported. 

• Assessing AEFI case reports received during stipulated time period.

• Assessing number of events and reporting rate per 1,000 or 10,000 or 100,000 doses of vaccine used.

• Analyses by the type of AEFI 

• Analysing programme errors by number and rates per 100 or 1,000 doses of relevant vaccines used. 

• Compare the rates with available or known background rates.  ​

Data analysis could be carried out by the responsible focal persons at different levels in the immunization safety surveillance system: 

• at the district level by AEFI COORDINATOR  and relevant staff

• at national level by the NIP and SFDA. 

Analysis of data at district level is important to identify the programme errors. This helps to carry out corrective action in a timely manner. Table 6.1 describes the type of analysis and the purpose.

​

Before analysis of the line list at the national level, it is important to re-check the case definitions adopted by the reporting sources. The case should fit into a case definition such as the Brighton collaboration case definitions (www.brightoncollaboration.org) or any definition selected by the National AEFI Committee.

Line lists should be used to sort data by place, person and time. Analysis should be done by antigens by type of reported adverse events (e.g. high fever, abscess) after stratifying data. Number of doses administered for each antigen is the best denominator for calculating reported AEFI rates for each antigen in a given time period (by month, quarter or year). Various denominators and their limitations are described in table 6.2. Analysis can be expanded to AEFI rates by first or second or third dose, when the antigen is administered more than once. For this, the number of doses administered of the given antigen by first, second or third need to be used as the denominator.

Multiplier: Use of proper multiplier in data analysis is important and also varied by purpose and level of analysis. At local level, percentage (x100= %) is the best choice, whereas at state and national levels, one may use 1000, 100,000 or million as multiplier. For common, minor vaccine reactions, percentage is recommended and for rare serious reactions, 10,000, 100,000 or 1,000,000 (million) can be used. ​

Available expected rates for each type of AEFI for a given antigen is provided at https://www.who.int/teams/regulation-prequalification/regulation-and safety/pharmacovigilance/health-professionals-info/reaction-rates-information-sheets. This can help to make decision on corrective action to be taken on reported AEFIs. It is also important to know about background rates of reported medical events in the country. Comparison of background rates with reported rates of AEFI will guide to a possible hypothesis of a coincidental event. For example, febrile seizures with bacterial or viral infection aetiologies are common among young children and may also occur following some vaccines such as DTwP. Therefore it is important to know the rate of febrile seizures due to other reasons and expected rates following a given antigen.

If the values exceed the expected background rates, then one should consider true increase or coincidence due to ongoing other diseases. ​

The AEFI surveillance system performance needs to be regularly reviewed at all levels to ensure that the system is sensitive enough to identify and respond to AEFI rapidly. The “standard overall" indicator proposed to determine the quality of AEFI surveillance at all levels is, “Individual serious AEFI** reporting rate in million total population from a country/ sub-national area per year".  This is calculated as

​Notes: The initial target***proposed is at least 1 serious report cases per 1,000,000 population per year.  The sub-national area/country is defined according to the functional requirements and setup of the national AEFI surveillance system.  

**An event that results in death, is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/ incapacity, or is a congenital anomaly/birth defect. Any medical event that requires intervention to prevent one of the outcomes above may also be considered as serious. 

***This will be revised based on periodic reviews

Some of the other key indicators that help to monitor the performance of the system include

• Timeliness and completeness of AEFI reporting  

• Percentage of AEFI cases reported on time (< 24 hours of notification) to the national level

• Percentage of serious AEFI cases investigated on time (< 48 hours of onset) using standard formats.

• Number (%) of AEFI investigation conclusions supported by findings of special tests (clinical specimens, Post-mortem findings (among AEFI deaths), lab findings for vaccine samples)

• Number (%) AEFI cases where final classification including causality assessment by AEFI committee is completed within 30 days of receipt of all documentation from  districts

• Number (%) AEFI cases reviewed by National AEFI committee following receipt of reported AEFI cases from region at National level.

• Number (%) AEFI cases reviewed by National AEFI committee and not assessable due to lack of information.

• Response to AEFI by the program particularly those related to programme error​

WHO has developed an AEFI data management e-Learning course that can be accessed here https://gvsi-aefi-tools.org/elearning.html ​

This section is a short introduction and practical overview of the purpose, process and classification of AEFI cases after causality assessment  A comprehensive guide and background to causality assessment has been published by WHO and can be accessed online at http://www.who.int/vaccine_safety/publications/gvs_aefi/en/

Causality assessment is the systematic evaluation of the information obtained about an AEFI to determine the likelihood that the event might have been caused by the vaccine/s received. Causality assessment does not necessarily establish whether or not a definite relationship exists, but generally ascertains a degree of association between the reported adverse events and the vaccine/vaccination. Nevertheless, causality assessment is a critical part of AEFI monitoring and enhances confidence in the national immunization programme. Causality assessment is important for:

​• identification of vaccine-related problems;

• identification of immunization error-related problems;

• excluding coincidental events;

• detection of signals for potential follow-up, testing of hypothesis and research; and

• validation of pre-licensure safety data with comparison of post-marketing surveillance safety data.​

The cases for which causality is ascertained include

• Serious AEFI

• Clusters & events above expected rate/ severity

• Evaluation of suspected Signals

• Other AEFI (if required)as decided by reviewing team / committee including

                  o  If immunization error is suspected 

                 o Significant events of unexplained cause within 30 days of vaccination

                 o Events causing significant parental or community concern (e.g. Hypotonic Hyporesponsive Episode (HHE), febrile seizures etc.)​​

Prior to causality assessment, 

• The AEFI case investigation should have been completed

• All details of the case such as case report form, case investigation form (annex 3), completed clinical case record, lab reports, autopsy report,  details of field investigations etc. should be available at the time of assessment

• There must be a “valid diagnosis” which is which the extent to which the unfavourable or unintended sign, abnormal laboratory finding, symptom or disease is defined.

With inadequate or incomplete case information, an adequate causality assessment cannot be performed or if attempted, the AEFI may be deemed unclassifiable or not assessable due to lack of information.

Even with complete information the AEFI may be categorized indeterminate due to the lack of clear evidence of a causal link (e.g., a new event), or conflicting external evidence or other inconsistencies. Sometimes even with adequate information, AEFI may be deemed unclassifiable or not assessable due to inability to proceed with the assessment. Nevertheless, these assessments should be recorded because the reporting of more cases may lead to a stronger signal and a plausible hypothesis, or stronger refutation of any link. ​

Figure 7.1 Final classification of cases after determining causality​

​

Causality assessment in Saudi Arabia is done by a national reviewing team/ committee that is

• Independent

• free of real or perceived government, industry conflicts of interest

• Has broad range of expertise in the areas of ‘infectious diseases, epidemiology, microbiology, pathology, immunology, neurology, vaccine program.

• The committee has written terms of reference (ToR)

In summary, causality assessment of serious cases needs high levels of expertise and will be done by an expert committee only at the national level. An assessment usually will not prove or disprove an association between an adverse event and the immunization. It is meant to assist in determining the level of certainty of such an association. A definite causal association or absence of association often cannot be established for an individual event.​

Responding to AEFI may involve immediate short-term activities or/and long-term follow-up activities. Follow-up activities should be based on findings of investigations, causality assessments and recommendations by the investigation/expert committees.

Proper and early treatment should be provided to patients regardless of the diagnosis. Case management and referral will vary depending on the seriousness. Mild symptoms such as mild fever and pain are likely to be of short duration and can be managed by assuring and educating parents during immunization. If parents return to seek medical attention, these cases should be documented and reported in the standard form. In case patients need hospitalization, a clear system for referral should be in place.

Table 8.1 Actions to be taken upon completion of the investigation/causality assessment

​

Depending on the nature of the event(s), the number of people affected, and community perceptions, an investigation may be conducted. In general, it is not advisable to discontinue the immunization programme while awaiting the completion of the investigation. If AEFI causality is not established – depending on the nature of the event, its extent and whether it is ongoing – a further investigation or epidemiological study may be warranted. However, it must be accepted that in some cases the relationship to vaccine will never be clear.

Communication and training are two important follow-up actions that have long term implications.​

Communication makes stakeholders aware of the process at each stage of the Investigation. The identification of particular interest groups and their representatives should comprise a part of an overall communication strategy. Decisions including what, whom and how, should be part of an overall communication strategy.

Need for improved communication

Concerns are frequently raised about vaccines and immunization programs by members of the general public and in the media. These concerns can be serious and are often misplaced. The graphic below (Fig 9.1) illustrates some of the factors that may trigger public concerns; hence the need for improved quantity, quality and targeted communication about vaccine safety.​

Fig 9.1 Factors triggering public concerns to immunization

​​​

Challenges to effective communication

Challenges that need to be overcome with effective communication include among others:

• Communicating the decline of childhood infections and deaths from VPD

• Parents view that infectious disease is a thing of the past

• Introduction of new vaccines and related information gaps

• Mass campaigns or Supplemental Immunization Activities (SIAs)

• need for transparency and accountability​​

Communication with parents, other members of the community, health staff and media need to be carried out under all circumstances. They should be kept informed about the investigation, results and action taken already or going to be taken regarding the AEFI. It is crucial to highlight the benefits of immunization while communicating on AEFI with the public and stakeholders. 

Key points to consider when communicating with the vaccine recipient (patient or client) or parents and guardians of the patient, community and health staff are;

• Listen to the client, parents or guardian and their concerns empathetically.

• Reassure and support the client, parent or guardian but do not make false promises.

• Assist the client, parents and guardian for hospitalization if necessary.

• Frequent communication with the client, parents or guardian regarding the progress of the patient.

• Prepare a fact sheet on adverse event for the client, parents or guardian, community, health staff and media. 

• Build up and maintain relationship among health staff, community and media. 

• Inform the individual client, parent or guardian about possible common adverse events and how to handle them.

• Continuously communicate with the client, parent or guardian and community during the investigation period to assure understanding the risk-benefit of vaccination.​

​AEFI can have repercussions on the entire routine immunization programme as well as campaigns. Where medical interventions are necessary, they should be carried out as rapidly as possible. Suppressing reports of AEFI or slow reaction can cause considerable damage to the immunization programme in the long-term. Messages relating to adverse events must be disseminated rapidly to prevent rumours spreading.

Once an AEFI has occurred, responses should include the following communication elements: 

• Communicate immediately with the MOH, and other high officials.

• Provide the parents with factual information. Remember that some parents may seek information elsewhere and you may lose credibility if you do not provide a trustworthy and technically sound response. The public and the other stakeholders have a right to know exactly what happened.

• Reassure parents, caregivers and adults that necessary measures are being taken so that the members of the community and caregivers are informed of what is happening.

• Communicate the results of the investigation to the programme managers and to the EPI officers at all levels.

• If the AEFI was caused by immunization error, tell the public what steps are being taken to prevent similar events in the future.

• Broadcast an official statement about the event on radio and television and publish a statement in newspapers.

• Repeat the message to dispel all fears.

• Constantly reassure the public of the safety of vaccines.

• Communicate among all level of health authorities involved.

• Reinforce their knowledge, ability, skills and performances.

• Update them on investigation process, progress and findings. 

• Reassure the staff of ongoing confidence in the immunization programme; quality of the vaccine and their services provided 

• Do not blame health care worker, instead focus on the correction and quality of the NIP program.​

Vaccine safety information needs to be shared with other stakeholders in order to ensure dissemination of correct information and thereby ensuring the smooth functioning of national immunization programme. Depending on the need stakeholders mentioned below will be given preliminary information at initial stage and final report after completion of investigation and causality assessment at a later stage.

• Saudi Food and Drug Authority  (SFDA)

• AEFI Committees at all levels

• Politicians

• Professional associations

• Universities and hospitals 

• International agencies and development partners

• Manufacturers ​

The media is an important gateway to inform the public and shapes their view and attitudes towards vaccines and immunization, especially including the occasional mass campaign. In the long-term, building partnerships with the media is key to keep the public regularly informed about immunization, its benefits and to motivate families and communities to make use of immunization services.

Advance preparedness

Effective communication with the media includes efficient coordination with the field staff, a plan, trained personnel, budget and practiced responses to potential issues around AEFI. Effective communication should be in place before an immunization campaign starts and as part of the on-going communication to support routine immunization programmes. 

A database of journalists 

It is essential to maintain a database of print and electronic media journalists covering health (local, national, international) with contact information. They need to be contacted and informed about the circumstances of the AEFI.

Information packages: 

Keep media informed through email or hardcopy by sending regular updates on any plans, programs and decisions. Sensitize media about health benefits of immunization and its impact globally and nationally. Prepare monthly or quarterly updates. Provide an updated information package with documents including Frequently Asked Questions (FAQs) on immunization in general, for specific disease and AEFI (Factsheet or a technical brief on a specific vaccine preventable disease etc.).

Draft media release: 

The draft media release must specifically answer the 6 W’s for journalists: 

• Who is affected/is responsible?

• What has happened? 

• What is being done?

• Where has it happened?

• When did it happen?

• Why did it happen?

• Will it happen again?​​

In the media release, mention the name and contact details of the AEFI focal person(s) and the name and contact details of the official spokesperson for further details should journalists have additional questions (at the end). 

A spokesperson system:

The district level shall be the first authority in releasing the information to the media. For this purpose the District Medical Officer shall be responsible for communicating the AEFI to media, public and stakeholders. This limits the possibility of conflicting messages coming from different sources. Ensure spokesperson has the important information.

Orientation workshops and field visits for media: 

Regular orientation workshops and field visits for journalists will help them achieve a better understanding of immunization advantages as well as the complexities of an immunization programme. This will also help to identify in advance the kind of questions or concerns that journalists specifically have. 

Media Management during an AEFI crisis

While every single AEFI must be investigated in detail, all AEFI cases may not be a crisis situation. A crisis often occurs from inaction rather than from taking appropriate action on AEFI. 

Monitoring of media: 

When an AEFI occurs, media should be monitored for authenticity of their reporting. The AEFI Committee should move very quickly to correct any inaccuracies. The AEFI Committee could take the following immediate actions:

• Analyze rumor, its level and potential to cause damage. 

• Anticipate how situations might evolve following response; prepare before responding.

• Deal with a simple mistake in reporting with a simple solution. If it is an isolated error, make a polite call to the reporter and offer to help the reporter with correct data and facts then and in the future. 

• If the rumor is confined to a small audience, correct it within that group only. If the error is widely reported, it may be necessary to call a media conference to present the correct facts before it leads to further damage. 

• Plan how to prevent future rumours.

Prepare a media release: 

An effective media release should include a complete account of the event, framed in its context (e.g. an isolated event or a cluster of AEFI or coincidental event). The media release should have;

• An outline of actions taken or planned (such as the AEFI investigation).

• A description of the cause of the event (but only when this is known with certainty).

• An assurance that corrective action has been taken or will be taken.

• Reference to any relevant publication, video material or web site.

• Sender’s name and spokesperson’s details. 

• Limited to one page of matter (400-500 words max).

• Short sentences (not exceeding two lines).

Quotes from key officials may be used after seeking their permission. The quotes must be positive and carry the key messages. 

Call a media conference: 

Media conferences may need to be conducted if AEFI is being reported extensively and widely and there is a need to provide accurate facts and de-sensationalize the story. A media conference enables all journalists to have the same information, thus there is then less likely of event being ‘sensationalized’. Consider the following steps when preparing for the media conference:

• AEFI Committee takes the lead but identifies who facilitates the press conference. 

• If there are several members on the panel, agree beforehand on the key message(s) in response to the AEFI.

• Agree on roles of each panel member beforehand, including the type of questions (media, political etc.) each panel member may best handle. 

• Panel members must avoid contradicting each other in the press conference unless it is critical to clarify something incorrect that has been said.

• Have a media kit ready and share it with journalists. The media kit may consist of a media release with all the essential information, supplementary background information, benefits and a set of frequently asked questions about immunization.​

Keeping promises to the media:

If it has been promised that media will be kept updated about the investigation findings, make sure the media is updated by the promised date. If the findings have been delayed, ensure the media is informed because they would be expecting answers.

Providing answers to unanswered questions:

During media conferences, if a question could not be answered for any reason – for example due to absence of data or if you were unprepared to answer the questions – get back to the media with the answers as soon as possible.

Keeping media informed about subsequent developments:

If any decision or action is taken at the highest levels following AEFI investigations or during the investigations and the public must know about it, keep the media informed though a press release or hard copy document.  The national immunization website moh.gov.sa/en/Pages/default.aspx can be used as an excellent interface to update the media.​

​In the context of immunization, rumour is defined as an unverifiable assertion that is circulating, or a statement without facts to confirm its truth. Rumours and misinformation about immunization are amongst the most serious threats to the success of any immunization programme. Once rumours start they can be very hard to stop. 

Some examples of rumours:

• “Vaccines are a contraceptive to control population or to limit the size of a certain ethnic group.” 

• “Vaccines are contaminated by the AIDS virus or mad cow disease.” 

• “Children are dying after receiving vaccines.”

Unless the rumour can very easily be contained and addressed you must refer the matter to your supervisors as quickly as possible. You will need to work under their direction - action may even need to be taken at the national level. The consequences of rumours can be serious and, if unchecked, they can travel quickly beyond your local area. 

Common causes of Rumours

• Inadequate information sharing by health care providers or 

• Failure to communicate correct information about vaccine effects and schedules, 

• Failure to check whether caregivers know and understand information, 

• Failure to give clients opportunities to ask questions 

• Parents/caregivers’ negative attitudes about immunization services

a) What you can do at the health facility

Under the direction of your supervisor:

• Meet with key opinion leaders (politicians, traditional and religious leaders, community leaders, other health workers).

• Organize meetings at sites where the individuals/groups are comfortable and feel at ease to ask questions.

• If there is a national mass media response, encourage your community members to watch and talk about it.

b) Words of advice

• React swiftly and adapt your ongoing activities to give a quick response.

• Develop strong relationships and trust with your community in advance (religious, social and media groups).

• Give clear and consistent messages.​

An infodemic is too much information including false or misleading information in digital and physical environments during a disease outbreak or immunization program. It causes confusion and risk-taking behaviours that can harm health. It also leads to mistrust in health authorities and undermines the public health response. An infodemic can intensify or lengthen outbreaks when people are unsure about what they need to do to protect their health and the health of people around them including vaccinations. With growing digitization – an expansion of social media and internet use – information can spread more rapidly. This can help to more quickly fill information voids but can also amplify harmful messages.

Infodemic management is the systematic use of risk- and evidence-based analysis and approaches to manage the infodemic and reduce its impact on health behaviours during health emergencies.

Infodemic management aims to enable good health practices through 4 types of activities:

​• Listening to community concerns and questions

• Promoting understanding of risk and health expert advice

• Building resilience to misinformation 

• Engaging and empowering communities to take positive action​​

​​​

​​