By Helen Petousis Harris 12/05/2020


Five months into the COVID-19 pandemic the conversation is shifting to vaccines. One of the key concerns voiced by some experts and public are that in the rush to get vaccines deployed, safety will be compromised. Here I outline, in part, the COVID-19 vaccine safety landscape of activities.

First, let me introduce you to some of the key entities tasked with advising, measuring, monitoring, and assessing vaccine safety. This is not complete but gives an idea of some of the agents involved. As you see, NZ has fingers in all the pies.

Entity

Role

Animal studies Animal models are used to study vaccines prior to moving into humans as well as throughout the life of a product. NZ have COVID-19 relevant animal models and relevant scientific expertise.
Clinical trial independent drug safety monitoring board (DSMB) All vaccine clinical trials have a DSMB. This is a group tasked with overseeing the safety of the vaccine. Ideally, they will have diverse expertise and should include a biostatistician. For COVID-19 vaccines it is recommended that there be persons with expertise in rare disease epidemiology. NZ has experience with all phases of vaccine clinical trials and has many individuals who have served (and are serving) on DSMBs.
Country pharmacovigilance system This is a system for receiving and assessing reports of adverse events that follow drugs, including vaccines. In NZ this system is considered very well developed and is the responsibility of MedSafe. Reports go to the Centre for Adverse Reactions Monitoring (CARM).
Country level active safety surveillance Some countries have systems that can monitor events in at least some of their population in near real time, and check exposure to a vaccine. NZ has this capacity (real time not in current use). A larger number of countries can assess potential safety events retrospectively. NZ are gold standard in this space.
The Brighton Collaboration International collaboration since 1999 tasked with developing definitions and guidelines for potential adverse events following immunisation. Since 2019 they have had a contract with CEPI to develop tools to guide us through evaluating the safety of vaccines developed with new technologies. Since COVID-19 emerged they have increased their activities and are developing tools to help us assess COVID-vaccines. NZ uses these definitions and tools and has a member on the Science Board.
Regulatory agencies Regulatory agencies are tasked with having authority over safety to protect consumers. Examples include the US Food and Drug Administration (FDA) and the European Medicines Association. In NZ MedSafe are responsible for this. Vaccines must be evaluated and approved by a national regulatory authority before they can be used.
The Global Vaccine Data Network (and other more localised initiatives) These are ‘distributed networks’. To assess potential rare adverse events very large populations are needed. These collaborations pull multiple countries together to conduct studies on huge numbers of people using administrative data and can compare the risks for very rare events between vaccinated and unvaccinated people. NZ is co-leading the Global Vaccine Data Network and the coordinating centre is at the University of Auckland. [publication coming, in press!]
The World Health Organization’s Global Advisory Committee on Vaccine Safety (GACVS). This is a committee of 14 experts from all regions of the world that meet twice a year (or when needed) to assess the safety of vaccines. They provide independent, authoritative, scientific advice to WHO on vaccine safety issues of global or regional concern. This year it is all about COVID-19 vaccines! NZ has a member on this committee.
The World Health Organization’s Strategic Advisory Group of Experts (SAGE) SAGE is the principal advisory group to WHO for vaccines and immunisation. This 15-member group advises WHO on overall global policies and strategies, ranging from vaccines and technology, research and development, to delivery of immunization and its linkages with other health interventions. For vaccine safety, SAGE takes the findings of the GACVS and makes recommendations. And yes, NZ has a person on SAGE as well!

With all these entities in play, this is how the safety of COVID-19 can be assessed:

  • The early assessments of vaccine safety occur in animal models and Phase I human trials. Here the investigators can look for any theoretical safety issues both by observing health outcomes as well as studying biological samples and conducting laboratory experiments. Some of what they look at will be guided by the tools provided by the Brighton Collaboration. Participants can be followed for an extended period of time. When confident with the results from the small numbers of participants they may move to Phase II while still monitoring Phase I.
  • Phase II trials have hundreds of participants. This will likely be a randomised trial with half of the participants getting a placebo or a different vaccine. It is an opportunity to see safety outcomes in a larger group. All going well, and no indication of serious adverse events caused by the vaccine, Phase III may commence. Again, Phase II participants can continue to be monitored.
  • Phase III trials for vaccines usually include tens of thousands these days. However, this is an emergency. At this point we may only include a few thousand so rare events cannot be excluded.

Below is an example of how we can manage the monitoring of safety for less common events when the number of trial participants is fewer than normal.

 

Case Study – the NZ MeNZB vaccine.

During the 90s and into the 2000s NZ had a devastating meningococcal disease epidemic. There was no suitable existing vaccine available so a tailor-made vaccine was developed through a partnership (NZ government, University of Auckland, Norwegian Institute of Public Health, and industry). It was tested in NZ and rolled out to the highest risk members of our population after only a few thousand people had received the vaccines.

To do this safely an intensive vaccine safety monitoring system was set up. All people in the age group receiving the vaccine who went to hospital were assessed for their vaccine exposure. Also, a proportion of general practices provided data on visits so that exposure to the vaccine could be assessed. Comparisons were made between vaccinated and unvaccinated people to see if there were any safety signals. This happened in near real time and provided high quality data that reassured us about the vaccine’s safety profile.

I would not want to see a COVID vaccine initially deployed in countries that do not have the systems to do something akin to the MeNZB intensive monitoring up and running.

How safety is monitored beyond the first trials

  • Phase IV studies or post marketing surveillance is where we can examine safety in a much larger population. While we can use approaches such as the one described above, we can also do cross-country studies that include millions. These studies will be essential during the deployment of COVID-19 vaccines and ideally conducted rapidly and frequently.
  • Tools and recommendations for asking the right questions during these studies are being developed by the Brighton Collaboration and should be used in all trials and Phase IV studies.
  • The GACVS will ask for data all the way through this process and evaluate it constantly. They may ask for more data.
  • Regulatory agencies will review the data all the way through this process and evaluate it constantly. Before a vaccine can be used in NZ MedSafe must approve it.
  • SAGE will provide guidance based on all information available to them.

As for time… These are not normal times, these are emergency times. Here are several reasons why this can be done faster than conventional vaccine timelines (I blogged about it here already)

Why it may be possible to develop a COVID-19 vaccine fast

  1. There is a stupid amount of money being thrown at this problem without the expectation of return on investment
  2. There are an unprecedented number of brilliant minds, biotech companies, academic institutes, and big multi-nationals on this
  3. The aforementioned are collaborating like never before and technology is being shared
  4. Activities are being expedited and run in parallel.
  5. We have technologies today that we did not have five years ago
  6. We have already demonstrated that all of the components can be achieved

The desperate need for an Ebola vaccine galvanised us

In less than 12 months, 12 clinical trials running the gamut from a “first in man” dosing study to a Phase 3 efficacy trial had been conducted. “That has never happened,”

[here for that  Ebola vaccine trial]

HOWEVER, any of the candidates can fail at any point, particularly in terms of either a safety outcome or effectiveness outcomes. The timelines commonly cited are based on all going well and it is this scenario we must be prepared for. We need to be prepared because if we are not we could have a vaccine on our hands that we can’t use because we did not organise ourselves to manage its deployment safely. Phase IV is as important as each of the other phases.

Assessing and monitoring the safety of COVID-19 vaccines is a multipronged attack that has already begun. There are no critical steps omitted. Of course, there are risks, there always are. However, we have some pretty good tools to do this well.