D Letter

Background

DiGeorge syndrome (also known as velocardiofacial syndrome or 22q11.2 deletion syndrome) is a genetic condition affecting approximately 1 in 2,000 newborns. It involves the deletion of DNA in the q11 region of the long arm of chromosome 22 during foetal development. Most cases occur as the result of a random gene mutation. However, in some instances the mutation can be inherited from a parent.  

The health implications of the deleted DNA sequence can vary between individuals. Common features include congenital heart defects, small or absent thymus, cleft or palate abnormalities, speech/language and developmental delay, hearing and visual problems, and learning difficulties. Immunodeficiency is also commonly associated with DiGeorge syndrome. This may be related to inadequate T-cell function, decreased levels of immunoglobulin or reduced antibody function.   

DiGeorge syndrome and vaccines

The decrease in immune function for many people with DiGeorge syndrome means that vaccination is particularly important to provide protection against vaccine-preventable diseases. However, it is important to recognise that the immune response to vaccines may be suboptimal meaning additional doses of vaccines may be recommended. Conversely, some vaccines (live-attenuated vaccines) may be contraindicated due to the potential risk of vaccine-related disease. 

Recommendations

The following guidance outlines recommendations for specific investigations and vaccines for children diagnosed with DiGeorge syndrome. This guidance has been developed as a collaboration between MVEC, Queensland Children’s Hospital, Royal Brisbane and Women’s Hospital and Perth Children’s Hospital. 

Immunological work-up and vaccination recommendations for children with 22q11 microdeletion (PDF)

Resources

• Guidance: Immunological work-up and vaccination recommendations for children with 22q11 microdeletion (PDF)
• MVEC: Immunosuppression and vaccines
• 22q Foundation Australia and New Zealand

What is it?

Diphtheria is a rare but potentially life-threatening acute illness caused by the bacteria Corynebacterium diphtheriae. This bacteria can produce a potent toxin which causes serious disease. It mostly commonly causes an acute respiratory illness characterised by a “pseudo membrane” which forms over the pharyngeal area (throat).

Other less common forms of illness caused by C. diphtheriae include laryngeal/tracheobronchial diphtheria, nasal diphtheria and cutaneous diphtheria.

What to look for

The incubation period is 2-5 days. Early symptoms include low-grade fever, lethargy and malaise. Affected people may develop a sore throat, which may cause pain on swallowing or a hoarse voice.

One to two days after symptom onset, a “pseudo membrane” develops in 95% of cases, which appears as a thick, grey and leathery membrane at the back of the throat. This is formed from cell debris and inflammatory exudate. Breathing difficulty may occur, especially if part of the membrane dislodges and obstructs the airway.

Toxin-related complications include myocarditis (heart muscle inflammation), neuropathy (nerve damage) and in rare cases, acute tubular nephropathy (kidney damage).

How is it transmitted?

Diphtheria is very contagious and is spread by inhalation of respiratory droplets from an infected person. Diphtheria can also be spread via skin lesions, in cases of cutaneous diphtheria, and the bacteria can also survive on environmental surfaces for weeks.  Asymptomatic carriers may transmit the bacteria.

Humans are the only known reservoir for diphtheria.

Epidemiology

In the pre-vaccine era, young children (< 10 years old) were at highest risk for contracting diphtheria.  Diphtheria previously represented one of the leading causes of death in childhood, with an associated mortality rate of 5-10%.

Diphtheria is now rare in high income countries with high vaccination coverage, but remains endemic in many lower income countries. Outbreaks across the globe continue to be an issue, with 16,000 cases worldwide reported in 2018.

Cases in Australia are more commonly associated with the return of international travellers.

Prevention

Diphtheria is vaccine-preventable, with protection available through administration of combination vaccines routinely administered via the National Immunisation Program (NIP) at:

• 6 weeks, 4 months and 6 months – Infanrix® hexa/Vaxelis®
• 18 months – Infanrix®/Tripacel®
• 4years – Infanrix® IPV/Quadracel®
• 12-13 years (Year 7) – Boostrix®

Additional doses of Boostrix® are recommended and funded for pregnant women during every pregnancy (regardless of how closely spaced). Further doses are recommended (not funded) for adults at ≥ 50 years of age, if their last dose was more than 10 years ago. Regular boosters are recommended every 10 years for travellers to high risk countries, and for some high-risk laboratory workers.

Injection site pain is commonly reported following diphtheria vaccination. This is usually mild and resolves within a few days. Uncommon side effects reported include headache, lethargy, malaise and fever.

Resources

• Australian Immunisation Handbook: Diphtheria
• CDC: Diphtheria
• AIHW: Diphtheria in Australia
• Australian Government Department of Health and Aged Care: Changes to the National Immunisation Program schedule from July 1 2023

Background

Like any medication in development, vaccine candidates must undergo rigorous testing procedures and scientific evaluation to prove not only their effect on the targeted disease, but also to determine their safety, before being licensed and registered for use in vaccination programs. In Australia, the Therapeutic Goods Administration (TGA) is responsible for assessing vaccines and other medicines for use in Australia.

Once vaccines have been introduced into the community, the safety and effectiveness of vaccines then continues to be monitored in the post-licensure phase through active surveillance programs and further post-licensure trials. This is to ensure that there is ongoing monitoring for how the vaccines are working in the ‘real-world’, noting they will be administered to a much larger and more diverse population than during the development phase.

Development phase

During vaccine development, initial safety testing of a vaccine candidate occurs in two stages. Stage one involves pre-clinical assessment in the laboratory. Stage two involves the evaluation of the vaccine candidate in three phases of human clinical trials. If a vaccine candidate is not deemed safe in any stage, it cannot progress into the further stages of clinical trials, with this data being reviewed by an independent data safety monitoring board (DSMB).

• Phase I clinical trials: the vaccine candidate is given to small numbers (25–50) of healthy adults with the primary goal of assessing safety.
• Phase II clinical trials: if the vaccine candidate is found to be safe in Phase I, it is then given to hundreds of people to determine how effectively it stimulates immune responses, the optimal dose regimen, and whether there are any side effects.
• Phase III clinical trials: if the vaccine candidate is found to be effective and safe in Phase I and II, it is then given to many thousands of people to test whether it protects large populations from the target disease and to determine if there are any uncommon or serious side effects.

A vaccine must pass all of these phases before it is registered for use by the TGA. Previously, approval of vaccines could take up to 10 years. However, the process has been streamlined throughout the COVID-19 pandemic and can now be completed in under 12 months, noting all of the appropriate clinical phase trials and data requirements from the regulators have not changed.

Post-licensure phase

Despite the extensive safety testing undertaken in clinical trials before a vaccine is licensed, some side effects are so rare, they cannot be detected in a trial population (e.g., such as with thrombosis with thrombocytopenia syndrome [TTS] following COVID-19 adenoviral vector vaccines). In addition, the efficacy of a vaccine may be different when given to a larger and more diverse population compared with those who participated in the clinical trial (e.g., due to the presence of underlying medical conditions, different age groups etc). For these reasons, assessment of safety and efficacy continues to be monitored in post-licensure assessments through:

• further clinical trials
• surveillance of the impact of the vaccine on the disease it aims to prevent using networks such as PAEDS
• surveillance of adverse events following immunisation using systems such as AusVaxSafety and reporting services like SAFEVAC and SAEFVIC.

What happens if a problem is suspected?

Any suspected vaccine safety signals undergo a thorough investigation by the TGA, with the support of the jurisdictional vaccine safety services.

If a suspected problem could be serious, authorities will consider a range of actions including modifying the product information (PI) and if extremely serious it may include suspending use of the vaccine during the investigation.

Provisional approval

Provisional approval has been the formal pathway used in Australia for speeding up access to COVID-19 vaccine candidates using preliminary clinical data. The provisional pathway allows for the temporary registration of promising medicines or vaccines based on early data, where the benefits of early access (such as in a pandemic), outweigh any risks.

It is very important to note that this evaluation process remains a full review and a vaccine is still required to pass all the same phases of clinical trials and meet the same requirements for safety and efficacy as any other vaccine in development.

As further clinical data to confirm the safety of a vaccine becomes available, full registration can then be granted (On April 21, 2023 Spikevax (Moderna) was transitioned from the provisional pathway to full registration).

Health Technology Assessment (HTA) of vaccines

Whilst vaccines are undergoing development and regulatory approval, in parallel they also need to undergo health economics assessment if they are going to go onto the National Immunisation Program (NIP). In Australia this assessment of vaccines is undertaken by the Pharmaceutical Benefits Advisory Committee (PBAC).

This pathway was not utilised during the COVID-19 pandemic, due to the speed and complexity of the public health emergency, but PBAC approval will be required for all new vaccines that are coming down the pipeline. As part of this assessment, ATAGI provides advice to the PBAC regarding how these vaccines may be best utilised in the Australian context, taking into account vaccine effectiveness, safety and equity.

Resources

• MVEC: Vaccine platforms
• MVEC COVID19 Road to a Vaccine Podcast, Episode 7: The importance of regulatory bodies in the development of vaccines, with Professor Norman Baylor
• MVEC COVID19 Road to a Vaccine Podcast, Episode 16: COVID19 vaccine candidates regulatory process update, with Professor Norman Baylor
• Australian Academy of Science: How are vaccines shown to be safe?
• The International Coalition of Medicines Regulatory Authorities: ICMRA statement about confidence in vaccine safety and effectiveness (for healthcare professionals)
• The International Coalition of Medicines Regulatory Authorities: ICMRA statement about confidence in vaccine safety and effectiveness (for the general public)

Drive-through immunisation clinics are an alternative venue for supporting vaccine delivery. A drive-through clinic can assist members of the community to continue to receive recommended immunisations whilst maintaining physical distancing.

A drive-through clinic may not be a setting that is recommended for all patients. It is important that patients be screened for their suitability to use a drive-through service prior to immunisation. Pre-screening of patients can identify previous immunisation reactions, history of vasovagal reactions or needle phobia.

Running sessions by appointment may allow for planning the type and amount of vaccines required and also allows the flow of patients to be staggered in order to prevent traffic congestion.

Preparation for drive-through clinics

There are many different factors that need to be considered when setting up for this type of immunisation venue.

The location

Consider a location within close proximity of the GP service or health care facility (if applicable). An ideal location would allow for a 1-directional flow of traffic in order to avoid congestion and ensure the safety of roaming staff members. Each individual parking bay should allow enough room for all 4 car doors to completely open without any obstructions (to ensure full access to each patient should AEFI occur).

Equipment

Carefully consider the equipment required to set up and maintain a drive-through clinic. Equipment should include clear signage, bed/chair to manage adverse events if required, an anaphylaxis response kit, essential paperwork, (such as pre-immunisation checklists and vaccine side effects forms), equipment to maintain the cold chain, as well as any equipment necessary to prepare and administer vaccines. Remote access to patient records and the Australian Immunisation Register (AIR) is recommended to allow for review of immunisation records. as well as appropriate documentation of any vaccines administered.

Staff

Staff may include nurse immunisers, as well as medical and administrative personnel.

The cold chain

Storage of vaccines in a drive-through clinic setting must comply with the cold chain recommendations set out by the vaccine manufacturer.  The time between vaccines being removed from purpose-built vaccine fridges to being administered should be as short as possible.

During a drive-through immunisation session

Immunisation history, pre-immunisation checklist, possible vaccine side effects and suitability for immunisation must be reviewed and discussed prior to vaccination.

Emergency equipment (anaphylaxis response kit) and a telephone must be readily available should they be required.

Correct injection technique is essential, ensuring that the entire limb is exposed and correct anatomical landmarks identified to locate the correct injection site. If a patient cannot be safely immunised in the car (eg: child seated in the middle car seat) or is not a suitable candidate for in-vehicle immunisation then they could be immunised out of the car in a chair, then returned to the car to wait for the recommended 15 minute waiting period. Patients should be advised not to get in and out of their cars whilst parked.

Post-immunisation in a drive-though session

Following immunisation, patients must remain at the vaccination venue for at least 15 minutes and should be advised to avoid driving for at least 15 minutes following vaccination. Patients waiting in their vehicles should be instructed to use the car horn to gain attention in their 15 minute observation period if required. All vaccines should be recorded on the AIR and appropriate documentation should be completed and provided to the patient.

Resources

• MVEC: Cold chain
• MVEC: Shoulder Injury Related to Vaccine Administration
• MVEC: Shoulder Injury Related to Vaccine Administration (SIRVA) eLearning package
• National Vaccine Storage Guidelines ‘Strive for 5’
• MVEC: Administration of injected vaccines- correct technique
• ATAGI Clinical Statement on Vaccination Observation Time
• ATAGI statement on considerations for establishing drive-through COVID-19 vaccination clinic sites