Covid-19 vaccines: Safety is top priority, but what is safety?

It is a matter of weighing benefits and risks and finding a right balance after doing due diligence

A child in Pakistan getting the polio vaccine. The writer says that perhaps we should use our current low-transmission breather to get vaccinated against Covid-19, when the treatment is available in Singapore, so that we can emerge stronger.
A child in Pakistan getting the polio vaccine. The writer says that perhaps we should use our current low-transmission breather to get vaccinated against Covid-19, when the treatment is available in Singapore, so that we can emerge stronger. PHOTO: AGENCE FRANCE-PRESSE

Would you take the Covid-19 vaccine, if it's available?

With the announcements of three Covid-19 vaccines achieving excellent rates of effectiveness, that is the question everyone is asking themselves.

The United States' Food & Drug Administration (FDA) will meet on Dec 10 to discuss the emergency use authorisation (EUA) of Pfizer's Covid-19 vaccine. If approved, Covid-19 vaccination for the highest risk groups could start in the US before Christmas.

Whether a vaccine should be used depends on several critical factors. Vaccine effectiveness is the obvious first step. However, it must be considered together with vaccine safety.

Vaccine safety is absolutely essential when considering vaccinating millions of people. So, what should we know about Covid-19 vaccine safety, and how should we think about it?

It is useful to first ask: "What is safety?" We could start with a dictionary definition: "The condition of being protected from danger, risk, or injury."

I suggest a pragmatic definition: Safety is finding an acceptable balance between risks and benefits, after doing due diligence.

This approach allows us to move forward, rather than getting stuck in analysis paralysis. After all, we make risk-benefit decisions every time we get in a car, board a plane, or cross the road. We manage the risks by putting in place systems to ensure road and air travel is as safe as possible.

We accept the risks when we get on an airplane, because the alternative would be a very long journey by road or sea, or not going anywhere at all.

We make similar risk-benefit judgments in medical practice. Vaccine safety is no different. Can we give an absolute guarantee that no one will ever experience any side effects or be harmed by a vaccine? Obviously not. Vaccines are medications, and all medications have risks and side effects, as well as situations when they should not be used.

The issue of side effects

So, what side effects should we look for when considering whether to use a vaccine?

There are two categories: danger and discomfort. Most of us who have had influenza vaccines are familiar with the discomfort; a sore arm for one to two days, a "fluey" feeling of fatigue, achiness and headaches.

Do vaccines cause fever? It depends on age group and the vaccine. For the influenza vaccine, fever can occur in 12 per cent of children aged one to five, in 5 per cent of those six to 15 years old while in adults, no difference was observed compared with placebo, or dummy.

Very rarely, more serious events with long-term consequences, even death, can occur after vaccinations. This is known and accepted in medical and public health practice because the alternative is the disability and death caused by the actual infectious disease itself in much larger numbers and scale.

The problem for vaccine programmes is that their very success breeds complacency, and a loss of urgency for the vaccine when the disease is no longer seen.

Among serious adverse events from vaccines, yellow fever vaccination can cause liver or brain inflammation for three out of a million persons vaccinated. The people who get the yellow fever vaccine nowadays are travellers to South America and sub-Saharan Africa, and populations in those endemic countries.

Yellow fever sounds like an exotic disease, and we may hesitate to vaccinate travellers at higher risk for vaccine complications. But what is rarely appreciated is that yellow fever used to be far more widespread and devastating; the last yellow fever outbreak in the US occurred in 1905 in New Orleans, and Philadelphia lost 10 per cent of its entire population to yellow fever in the 1793 outbreak.

Yellow fever is spread by Aedes aegypti mosquitoes, familiar to us as the vector for dengue fever. However, unlike dengue which has a fatality rate of 1 in 1,000, yellow fever still carries a fatality rate of 20 per cent to 60 per cent among those severely ill.

So, the safety considerations for vaccination must take into account the other side of the equation: What happens without vaccination, not just for the individual, but also for entire cities and countries?

Polio, which caused epidemics leaving children and adults permanently paralysed, was stopped only by vaccination. The Sabin oral polio vaccine contains a live, weakened virus, which rarely causes vaccine-associated paralytic polio, at four in a million. Vaccine-associated polio happens to 400-500 persons per year worldwide, but when compared with the 350,000 polio cases in 1988 at the start of polio eradication efforts, the risk-benefit clearly favours vaccination.

If a serious event occurs after someone gets vaccinated, another challenge is to determine whether the event is caused by the vaccination, or whether it is a coincidental occurrence.

We have had influenza vaccines for over seven decades, giving over 150 million doses per year.

Yet when media reports surfaced of deaths following flu vaccination in South Korea, vaccination was paused until autopsies on 46 of the cases provided evidence that the deaths, mostly among people in their 70s and 80s, were likely to have been caused by existing medical conditions, and not the vaccine.

Events are top-line numbers, numerators. We need denominators to understand the true risk. The 50-90 deaths occurred on a denominator of 19 million Koreans vaccinated, so we must know the baseline rate of deaths to know if there are grounds for concern.

Risk of unknown unknowns

What are the real challenges with vaccine safety for Covid-19 vaccines? Firstly, both front runners for FDA approval, the vaccines by Pfizer and US biotech company Moderna, use a novel mRNA platform which has not been previously used for infectious disease vaccines, although mRNA vaccines have been studied as therapy for cancer.

Other Covid-19 vaccines employ adenovirus vectors, another relatively new platform. All these technologies have allowed incredibly quick progress, but come with a risk of unknown unknowns, which is being monitored.

Secondly, even with Covid-19 vaccine trials recruiting over 30,000 participants, rare risks of vaccines such as anaphylaxis (a severe allergic reaction that is potentially life-threatening) may not be brought to light.

In general, if an event occurs with a probability of one in 10,000 people, we need a minimum of 30,000 participants to detect such an event, or have reasonable certainty that it has indeed not occurred.

The current Phase 3 results with 15,000-22,000 participants in the vaccinated groups give only the ability to assess the risk of adverse events which occur at a probability of one in 5,000, to one in 7,000.

Anaphylaxis from influenza vaccine occurs at a rate of 1.3 per million. We would need to vaccinate more than three million people to confidently detect or exclude the presence of such a rare adverse event. No research trial can recruit three million participants, so such rare events are monitored after approval by regulatory agencies like the FDA, or its counterpart in Singapore, the Health Sciences Authority (HSA).

Assuming Covid-19 vaccine carries a similar risk of anaphylaxis, if we were to vaccinate five million people in Singapore, we could see five to 10 cases of anaphylaxis, and we'd have to be prepared. Such is the trade-off which accompanies the far greater benefit of protecting us all by vaccination.

As part of due diligence for safety in fast-tracking Covid-19 vaccine approvals, the FDA put in place a two-month waiting period after the second dose of Covid-19 vaccine was given, to see if any auto-immune or other unexpected side effects develop.

So, when Pfizer filed its EUA application on Nov 20, it had already completed this waiting period enforced by the FDA. The full monitoring period for well-conducted vaccine studies will be at least one to two years. All these safeguards provide further assurance of vigilance over vaccine safety.

What should Singapore do?

So, what does this mean for Singapore? When Covid-19 vaccine supplies arrive, should the health authorities start vaccinating or wait? If you are on the receiving end, should you take the Covid-19 vaccine, wait, or refuse?

It could be argued that from the safety standpoint, we should wait and not be the first adopters.

In Singapore, our community transmission rates have fallen to zero or near-zero for some time. This low rate has been achieved as a result of much hard work and expanded testing, and it bought us some time.

Other countries face much higher rates of Covid-19 spread. With strained healthcare systems and renewed lockdowns, there is much greater pressure to use vaccines as soon as possible, and it makes sense to do so.

When Covid-19 vaccines are deployed in millions of people, we should very quickly accrue enough data to determine rates for even rare vaccination risks.

But should we wait that long?

Vaccines take time to generate protective immunity, and most of the Covid-19 vaccines so far are two-dose vaccines, given over three to four weeks.

If we are swamped by a Covid-19 second wave, most of our medical and public health resources will be consumed by patient care, contact tracing and quarantine. People may be hesitant to come for vaccinations if there is a risk of getting infected in crowds waiting for their vaccination.

Perhaps we should use our current low-transmission breather to get vaccinated, so that we can emerge stronger. Moreover, over time, the very tight controls wear on us all. We need to enable a calibrated return to economic and social activities.

These are not easy decisions to make, with so much riding on different considerations. But the challenge of how to use Covid-19 vaccines wisely is a good problem to have, for which we should be thankful. With evidence of 95 per cent efficacy, vaccines might turn out to be a game changer for this Covid-19 pandemic, as it has for other infectious diseases.

•Associate Professor Lim Poh Lian is head of the Travellers' Health and Vaccination Clinic at Tan Tock Seng Hospital, senior consultant at the National Centre for Infectious Diseases, and a member of the Ministry of Health's expert committee on Covid-19 vaccination.

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