How vaccine safety is monitored in SAPHOTO: GCIS

How vaccine safety is monitored in SA

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The South African Health Products Regulatory Authority’s (SAHPRA) recommendation at the weekend to lift the temporary suspension of the use of the Johnson & Johnson COVID-19 vaccine in the Sisonke phase IIIB implementation study, has rekindled hopes that the phased rollout of the vaccine will press ahead and more vaccine doses will soon get into more people’s arms.

The temporary pause of the J& J vaccine last week (April 13) in South Africa, gave rise to concerns about the vaccine’s safety and fears that the cautionary move would increase vaccine hesitancy. SAHPRA’s decision was in line with the Food and Drug Administration’s (FDA) decision to do the same in the United States following reports of rare adverse events. No similar adverse events have been reported in South Africa.

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The imminent lifting of the suspension in South Africa means the Sisonke study should start vaccinating people again within a few days. The study, part of stage one of the national vaccine rollout, aims to vaccinate half a million frontline healthcare workers. Around 300 000 healthcare workers have been vaccinated so far.

Registration for stage two of the rollout is underway.

On May 17, vaccination is scheduled to begin for five million citizens over 60 years of age, 12 million essential workers and those who have co-morbidities.

Spotlight asked Hannelie Meyer, Professor in the School of Pharmacy and Head of the South African Vaccination and Immunisation Centre at Sefako Makgatho University, and Florah Matlala from SAHPRA’s Pharmacovigilance Unit to explain how vaccines are monitored for safety after vaccines, including COVID-19 vaccines, are rolled out to the general public.

How does safety monitoring work?

SAHPRA and the Department of Health’s Expanded Programme on Immunisation (EPI) is central to South Africa’s monitoring and surveillance system. Reporting of adverse events following immunisation (AEFI) has always been part of the EPI’s monitoring and evaluation process. In 2017, the AEFI surveillance system was strengthened, with reporting and investigation responsibilities at district, provincial and national levels as well as in the private sector.

SAHPRA authorises, monitors and evaluates all clinical trials in South Africa.

researcher holding a vial. PHOTO: Sanofi Pasteur/Patrick Boulen
PHOTO: Sanofi Pasteur/Patrick Boulen

Meyer says, very strict safety monitoring, known as pharmacovigilance, takes place during all three phases of clinical trials when vaccines are tested for efficacy and safety. However, she says “no clinical trial can be powered to detect rare or very rare adverse events”. It is only when a vaccine is rolled out to large populations that rare adverse events can be picked up.

Safety monitoring continues when SAHPRA registers a vaccine for use in the general population. This is called post-marketing surveillance and “determines the long-term risks and benefits of the vaccine, and identifies if there are any rare or very rare AEFIs or AEFIs that are slow in onset (slow to manifest)”. Matlala says SAHPRA’s mandate includes ensuring that a pharmacovigilance system for health products is in place.

What is a rare or very rare adverse event? 

Rare adverse events are those occurring between 1 in 1 000 doses to 1 in 10 000 doses, while very rare adverse events are those occurring in less than 1 in 10 000 doses.

“For these events, one needs to do a risk assessment to weigh the risks and benefits of vaccination,” says Meyer.

Using the recent case of the rare blood clotting condition identified in 6 out of 6.8 million people who received the J&J vaccine in the US as an example, Meyer says the risk of thrombosis (blood clotting) following vaccination is less than 1 in a million people or 0.000088%, while the risk of thrombosis in severe COVID-19 is approximately 20% to 30%.

There are also other confounding risk factors that might have been present in these women, which is why the FDA is currently busy with an in-depth investigation of these cases, says Meyer.

“We know that for example smoking, injury, immobility, genetic factors and other medicines such as oral contraceptives predispose people to the risk of thrombosis. Furthermore, COVID-19 infection itself is associated with blood clots and one of the major causes of death, hence a much higher risk factor to consider.”

She says even if this rare blood clotting condition is associated with the vaccine, the risks of developing thrombosis from COVID-19 infection or dying from the disease is much, much higher than the risk of this rare event. The AstraZeneca COVID-19 vaccine, which is not used in South Africa, uses a similar approach to the J&J vaccine and although the FDA and the European Medicines Agency reported a plausible link between the AstraZeneca vaccine and thrombosis, this is also extremely rare.

Who is responsible for adverse event reporting and monitoring?

Meyer says all healthcare workers who provide immunisation services, those providing clinical treatment of AEFI in health facilities and clinical trial researchers are responsible for reporting AEFIs. Vaccine recipients are also encouraged to report AEFIs.

In addition, Matlala says that according to the Medicines and Related Substances Act 101 of 1965, as amended, pharmaceutical companies must monitor the performance of their medicines and vaccines on the market and report any adverse effects to SAHPRA.

Vaccine AEFI reporting and notification in South Africa takes place through passive surveillance or spontaneous reporting. Meyer says, “This system is useful for the identification of potential safety signals (concerns) for AEFIs that were unknown at the time of a vaccine rollout or that are unexpected. However, a disadvantage is that it does not collect data from all vaccine recipients, as in a clinical trial, and it is unable to differentiate between a real reaction following immunisation and any coincidental event.”

Vaccinations underway at Klerksdorp Hospital in North West. PHOTO: North West DOH/Facebook
Vaccinations underway at Klerksdorp Hospital in North West. PHOTO: North West DOH/Facebook

The EPI currently uses a paper-based system for AEFI reporting.

“In addition to the electronic vaccination data system developed for COVID-19 vaccine registration and recording of vaccination, an electronic system for the reporting of adverse events is now available,” Meyer says.

The Med Safety App is a mobile application available for Android and iOS devices, facilitating spontaneous reporting and enabling the reporting of suspected adverse drug reactions for medicines and AEFIs for vaccines. Matlala says the public can use the app to report on adverse drug reactions, but only health workers can use it to report AEFIs.

All AEFIs reported through the AEFI surveillance system are shared with SAHPRA. SAHPRA then uploads it to a global pharmacovigilance database called VigiBase® – a database maintained by the Uppsala Monitoring Centre under the umbrella of the World Health Organization International Drug Monitoring Programme – a worldwide collaboration of over 150 countries.

What is a safety signal?

A safety signal is when AEFI reports suggest a potential causal association between a vaccine and an AEFI, and when it is considered being of sufficient importance to justify investigation or verification. Meyer says the rare blood clotting condition identified after J&J vaccination in the United States is a signal of an unusual situation. This requires investigation, which the FDA is currently doing.

Meyer says the pooling of data from different countries once a vaccine has been rolled out to a large population (not just in a clinical trial) is best for signal detection. Future electronic reporting of AEFI in South Africa through the Med Safety App will allow this, as data from South Africa will be pooled with three other countries in Africa (Nigeria, Ghana, and Ethiopia). Any detected signals will be reviewed by a committee of experts from the four countries, with support from the regulatory authority in the United Kingdom, says Meyer.

She says “detecting and investigating any safety signal is an extremely important aspect of the safety monitoring of new vaccines”. It means precautionary measures can be taken such as using a vaccine in certain populations and not in others and ensuring necessary management protocols are in place, should a rare event occur.

Covid-19 Vaccine and Syringe. PHOTO: Cindy Shebley/Flickr
PHOTO: Cindy Shebley/Flickr

What happens when a serious or severe AEFI is reported?

When any adverse event is detected and reported, a multi-disciplinary healthcare team begins an investigation. All AEFIs must be reported within 24 hours of identification or when a vaccinated person informs their healthcare provider. All reported adverse events are monitored very closely, says Meyer.

First, symptoms arising from the adverse event are treated if necessary. A case investigation is then set up. All information and reports are collated for serious events and clusters and are usually completed within 48 hours after reporting.

The National Immunisation Safety Expert Committee then reviews all the information and assesses whether there is a real safety concern related to the vaccine, whether the event occurred coincidentally, and whether it was due to an underlying health issue. The COVID-19 Ministerial Advisory Committee on Vaccines also weighs in on assessments.

Matlala says depending on the outcome of an investigation into a serious adverse event, SAHPRA may request changes to the product information, including the package insert and the patient information leaflet. “These changes will stipulate specific contraindications for use, special precautionary measures to take or special warnings with the use of such a product,” she says.

In the case of the J&J implementation study, SAHPRA recommended that the pause be lifted provided certain conditions be met, including changes to the screening process to include specifically, participants who are at risk of any blood clotting disorder, and changes to the information provided to participants and the consent forms.

“There should also be measures in place to ensure monitoring of participants who are at high risk of a blood clotting disorder and the management of participants who do develop vaccine-induced thrombosis and thrombocytopenia,” says Matlala.

All healthcare workers who administer vaccines, including the COVID-19 vaccine, receive training on how to handle and administer the vaccine and manage and report any adverse events. For the COVID-19 vaccine, every vaccine administered is recorded in a national register and all vaccinated persons are provided with a vaccination card. Various systems are being implemented to allow any person who has received a COVID-19 vaccine to personally report any concerning AEFI. This includes electronic reporting using a mobile App.

What is the potential for an increase in vaccine hesitancy?

“The pause in the J&J COVID-19 vaccine rollout demonstrates that vaccine safety monitoring works extremely well, and in a perfect world that would build public confidence in vaccination,” says Meyer. “However, we don’t live in a perfect world, so the pause can potentially be harmful to vaccine confidence in general, and subsequently vaccine hesitancy will rise.”

She says the focus on the rare adverse event following J&J vaccination was having a negative effect on people’s perceptions. “However, the adverse event is extremely rare and people forget that the risks of severe outcomes from COVID-19 infection are much higher.

“Misinformation spreads very rapidly, especially on social media, which then fuels vaccine hesitancy and vaccine refusal amongst those people who do not verify information and indiscriminately share information within their own networks. This has the potential of having a devastating impact on public health.”

*Adele Baleta is an independent science writer and a member of the Vaccine Hesitancy Working Group for the National Advisory Group on Immunisation.

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