Sunday, 29 November 2020

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
By Lim Poh Lian, Published The Straits Times, 28 Nov 2020

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.

Singapore has no need to rely on one Covid-19 vaccine with several promising candidates in the race
With at least three drugs seeking emergency use authorisation, Singapore need not bank on a specific candidate
By Joyce Teo, Senior Health Correspondent, The Straits Times, 28 Nov 2020

With not one, not two, but three Covid-19 vaccines applying for emergency use authorisation across the globe, and several others in clinical trials, including a home-grown candidate, Singapore can be sure it will not have to put all its eggs in one basket to keep its people safe from the coronavirus. And it may also not have too long to wait.

Professor Ooi Eng Eong, deputy director of Duke-NUS Medical School's Emerging Infectious Diseases Programme, said: "We should use whatever vaccines with well-proven safety and efficacy as soon as possible to protect our population and return to our normal lives as much as, and as soon as possible."

In the past few weeks, news of promising interim late-trial results for three vaccine candidates has come thick and fast, helping to inject some joy into a world weighed down by a pandemic that has infected more than 61 million people and claimed over 1.4 million lives.

Pharmaceutical giant Pfizer and its German partner, BioNTech, were first off the blocks, announcing on Nov 9 that their vaccine candidate was more than 90 per cent effective in preventing people from getting the disease. This went up to 95 per cent when it released the first set of complete results on Nov 18.

Fast on its heels was US pharmaceutical firm Moderna, which said on Nov 16 that its vaccine candidate had demonstrated an efficacy rate of 94.5 per cent.

AstraZeneca was third in the vaccine race to announce it had a potential winner on its hands.

Last Monday, it said that the vaccine candidate it is developing with Oxford University had an efficacy rate of up to 90 per cent if a lower first dose was used with a regular second dose. Otherwise, with two standard doses, the efficacy rate was 62 per cent.

"To achieve 90 per cent to 95 per cent vaccine efficacy in outbreak conditions with a novel pathogen within a year of discovery is as remarkable as two golfers playing on a completely unfamiliar green, who have just hit holes-in-one," said Associate Professor Lim Poh Lian, the head of the Travellers' Health and Vaccination Clinic at Tan Tock Seng Hospital.

Health Minister Gan Kim Yong has said Singapore will work towards "securing a portfolio" of Covid-19 vaccines to cater to different segments of the population.

Asked which vaccine he was most excited about, Prof Ooi, principal investigator for Lunar- CoV19, the vaccine candidate being developed by Arcturus Therapeutics in the United States and the Duke-NUS Medical School here, replied: "I will take the first available licensed vaccine."

News that the three vaccine candidates can be 90 per cent to 95 per cent effective gave cause for optimism that the world could turn the corner in the virus battle. However, while the vaccines do prevent most people from falling ill with Covid-19, there is no data to show they stop a person from being infected, then passing the infection on even without getting sick; or how long they last.

"Asymptomatic Sars-CoV-2 infection in vaccinated individuals could still allow the virus to spread in our community and cause Covid-19 in unvaccinated individuals," said Prof Ooi.

Experts have stressed that no vaccine is perfect. So, while a good vaccine boosts a person's immune system to give them a headstart in fighting a disease, it may not confer 100 per cent protection, nor will it work on everyone. It can also wear off in time. People who received a shot against mumps or whooping cough, for instance, may still pass it on.

Even so, when enough people are vaccinated, and the virus cannot travel as easily from person to person – the entire community is less likely to get the disease. Prof Ooi said it would take time to determine if any vaccine can prevent the Sars-CoV-2 infection.

"We should thus sustain a pipeline of new vaccines so that we can find those that are most effective at sustaining protection against Covid-19 and possibly even eliminating Sars-CoV-2 from the human population," he said.

At a webinar hosted by The Straits Times on Wednesday, Singapore's chief health scientist, Professor Tan Chorh Chuan, said that Covid-19 vaccines on the cusp of being approved would completely shift the battle against the pandemic but they cannot eliminate all other measures.

"It'd be a game changer because it'd allow us to blunt, very substantially, many of the negative impacts of the Covid-19 pandemic," he said.

"But while it will be a game changer, it will not be a silver bullet. As all of us know, the supply will be limited."

It will probably be a year or two before enough doses are made available to vaccinate enough people around the world, he said.

In the meantime, the public will still have to adhere to safe distancing measures as there will still be a "very substantial risk of transmission and outbreaks".

Prof Tan, who is part of a 14-member committee formed recently to prioritise the people who should be given the vaccines as they become available, said a Covid-19 vaccine will allow the world to protect healthcare workers and older, more vulnerable people who are at higher risk of mortality.

One of the problems that health systems in many places have faced is that their medical staff become infected in the course of their work or in the community, thus reducing the healthcare workforce when it is most needed, he said.

Racing ahead

Right now, human trials of at least 48 Covid-19 vaccine candidates are in progress.

The success in harnessing new technology marks a turning point in the field, but also underscores that the hunt for a vaccine has entered uncharted territory.

Pfizer and Moderna's vaccines are the most novel, being based on messenger RNA (mRNA), a genetic blueprint which instructs human cells to make the coronavirus' spike protein to induce an immune response.

While DNA and RNA vaccines have been developed against other diseases, such as HIV, and gone through early stage trials, none has been approved for use in humans.

The AstraZeneca-Oxford vaccine is made from a cold virus known as an adenovirus that is derived from chimpanzees – so it is harmless to people, and genetically modified to carry a gene for the spike protein. Such vaccines have yet to be licensed for use in humans, though this technology has been around for many years.

The body makes use of the information encoded in the spike gene to make the spike protein, which then trains the immune system to recognise and react against this characteristic feature of Sars-CoV-2, said Prof Ooi.

The difference is that the vaccine developed by AstraZeneca and Oxford makes use of chimpanzee adenovirus to "carry" the spike gene while the other two vaccine candidates constructed the spike gene in the form of RNA, which is then taken up by the cells as a template for making the spike protein.

The form that the spike gene takes in these vaccines means that their storage conditions differ.

In the mRNA vaccines, the RNA of the spike gene is packaged inside lipid (fat) nanoparticles, which are less stable and, depending on the chemical composition of the lipids, would require lower temperatures to remain stable during shipment and storage.

As for the AstraZeneca/Oxford vaccine, the spike gene is encased inside the protein shell of the adenovirus, which is among the most stable forms of viruses in the world, and can thus be shipped and stored under refrigerated conditions.

This is why experts have said it is likely to have a wider roll-out than, say, Pfizer's mRNA vaccine, which must be stored in ultra-cold conditions.

However, doubts have been raised over the efficacy of this vaccine, as the developers have acknowledged an error in the vaccine dosage that led to some study participants getting a lower first dose, though this regimen turned out to be a winner. These are the people aged 55 and below, so it is not clear if this dosing regime would offer the same coverage for older people.

Storage that requires special freezers presents a major logistical challenge. Cost is also a factor in vaccine distribution.

AstraZeneca has promised to make no profit from its vaccine while the pandemic lasts. Its dose is reportedly cheaper – at about US$4 (S$5.40), compared with around US$20 for Pfizer's vaccine and between US$25 and US$37 for Moderna's vaccine.

The vaccine candidate from Arcturus and Duke-NUS is also based on mRNA. Arcturus has said it could be shipped out in the first quarter of next year.

Are these vaccines safe?

The speed at which Covid-19 vaccines are being developed has been described as incredible and extraordinary.

It is an unprecedented pace made possible by parallel processing, said Prof Ooi.

"Conventionally, each step of the vaccine development is done serially, one after another. This is so that vaccine developers can avoid committing large financial resources prematurely to a vaccine that may not work as desired," he said.

But the urgency of the Covid-19 pandemic caused many companies and teams to take on the financial risks and accelerate vaccine development. "Importantly, there have been no shortcuts in determining vaccine safety and efficacy."

Scientists have also been able to accelerate the Covid-19 vaccine development process because of vast improvements in vaccine technology, said Prof Tan.

The mRNA and adenoviral vector vaccines, for instance, can be designed, developed and tested much faster than by traditional methods.

He pointed out that the more common side-effects, such as pain at the injection site or fever after vaccination, as well as rare side-effects, will be picked up at the trials as they have been done at a very substantial scale. However, "some of the very rare side-effects and some of those side-effects which may take some time before they manifest will not be picked up right now".

This is why the planning does not end at the vaccination stage. "We track the sort of side-effects that arise following vaccination and try to pick up as early as possible any signs of very rare or serious kinds of problems, and that then we take action very quickly," he said.

"This is an area that regulators and medical systems around the world are looking at very carefully and there will be very intensive surveillance, if and when vaccinations begin."

At the start, Covid-19 vaccination could be approved or recommended for only some groups, for which data has shown the vaccine to be safe and effective, he added. Prof Lim, who is also a senior consultant at the National Centre for Infectious Diseases and a member of the Ministry of Health's expert committee on Covid-19 vaccination, said there is much hard work ahead, with regard to scrutinising vaccine safety, tolerability and duration of protection.

The experts will also need to analyse vaccine safety and efficacy in different groups, such as older adults, children, pregnant women, immunocompromised persons and those of various ethnicities, she said.

"There will be even harder work with practical aspects of vaccine delivery, and making it accessible to people who need it, and people who want it," said Prof Lim. "But there is good reason that with these vaccine clinical trial results, we finally have real hope that help is coming."


Vaccine development is a painstaking, methodical process, beginning with in vitro data (so-called test tube experiments) and in vivo data (in living systems, typically animal studies). Only then can vaccine companies conduct Phase 1 to Phase 3 clinical trials in humans.

Phase 1 trials

• Look at safety and the immune response generated in small numbers of human volunteers, typically several dozen. 

Phase 2 trials

• Compare different doses to find the best one to take forward into larger Phase 3 trials.

• Phase 2 also collects more data on safety and immune responses with larger groups, typically several hundred. 

Phase 2 and Phase 3 clinical trials

• Generally also have a placebo control group aspect, and are randomised, which means any participant has an equal chance of being given the vaccine or the placebo.

Covid-19 vaccines: Priorities, processes and practicalities
As vaccines become available, new challenges await, including managing delivery systems, tracking outcomes, and winning over those still hesitant about the benefits of vaccination.
By Lim Poh Lian and Benjamin Ong, Published The Straits Times, 1 Dec 2020

With Covid-19 flaring up again in many countries, and safe, effective vaccines likely to become available over the next few months, how do we deploy them wisely and well?

Globally, the Covid-19 Vaccine Global Access (Covax) Facility is working on vaccine access for all who need it, including low- and medium-income countries. This international collaboration aims to enable equitable distribution of Covid-19 vaccines through global risk-sharing and pooled procurement strategies.

Although there are over 70 vaccines currently in human trials, the history of vaccine development is fraught with candidates that perform well in phase one and two studies, but stumble at phase three, the final stage prior to regulatory approval.

Risk-sharing and pooled procurement protect countries from backing the wrong horse and winding up empty-handed with no vaccines for their people, and allow poorer countries a chance to get access to vaccines.

Safety and efficacy

Each country will have its own considerations regarding when and how to vaccinate its population based upon its circumstances. So, when should Covid-19 vaccines be used within Singapore, and how should we prioritise who gets the vaccines first when they become available here?

Safety and efficacy are our highest priorities, so Covid-19 vaccines should be recommended for use only after they have passed rigorous scrutiny by the health authorities and medical experts. This requires that the risk-benefit be favourable.

The goals of vaccination are to protect people from Covid-19 infections and its severe complications, to protect our communities from the public health impact of outbreaks, and to facilitate the safe reopening of our economy, society and borders.

The highest priority would generally be to protect healthcare staff and front-line workers, a sensible objective as it ensures that we can keep our essential operations functioning. These goals shape the formulation of our Covid-19 vaccination strategy: who should be vaccinated, when vaccination should occur and how vaccines are administered.

Initial supplies of Covid-19 vaccines will be limited because of strong global demand and urgent needs in countries facing Covid-19 surges. As vaccine production ramps up worldwide, and other vaccine candidates complete phase three trials successfully, vaccine supplies should eventually be sufficient for everyone living in Singapore to get vaccinated.

To this end, the World Health Organisation and other countries have articulated frameworks for which groups should get priority access to vaccines. Our prioritisation framework should be consistent with published international plans, as it is similarly anchored on two major dimensions of risk: the risk of getting infected with Covid-19, and the risk of severe complications or death from the virus.

Since healthcare staff and essential front-line workers have high risk exposure, giving them priority conserves our healthcare and essential services capacity. We know as well which segments of our community are at highest risk of serious infection, making them the most vulnerable, should they get infected.

Therefore, such vulnerable individuals, especially older adults and persons with medical conditions, should also be given priority as vaccine supplies become available. Our ultimate goal should be to enable everyone residing in Singapore to have the opportunity for vaccination.

With the pandemic raging around the world, we are likely to be able to analyse Covid-19 vaccine data for their efficacy and safety in specific segments of the population which are less well studied, particularly children and pregnant women.

While such data may take time to accrue, the large number of Covid-19 cases globally will likely give us much-needed data more quickly than in the case of other vaccines. Of note, vaccine manufacturers have made efforts to broaden the diversity of participants in research trials, specifically different ethnicities and older adults.

To date, early data has indicated that vaccine efficacy is high in adults over the age of 65, and that this seems consistent across age, gender and ethnicity.

Managing the vaccination process

As we will be aiming to vaccinate large numbers of Singaporeans over a relatively short space of time, managing the process will be a challenge.

Some of the issues that will be actively worked on include tracking who has been vaccinated, managing the cold chain because the mRNA Covid-19 vaccines will require storage at low temperatures of up to minus 70 deg C (colder than Antarctica!), and organising the flow of people coming for vaccination.

We will also need to be able to monitor vaccinated people for side effects possibly linked to the vaccine, and develop a process to assist the very few who do experience rare vaccine side effects.

There are some important unknowns that remain with vaccination. The first is how long immunity lasts after vaccination or infection. We refer to this as the durability of immunity. We already know that some recovered cases can have a persistent positive test for a while, but these are generally not considered reinfections. So far, we have not been able to culture live virus from such individuals locally.

Rare, true reinfections have been reported. But we should also see this in light of the fact that over 63 million have been infected, 43 million have recovered, and many countries are experiencing repeated waves of Covid-19 transmission. Therefore, if reinfections were truly common, we would expect to have seen more cases by now.

While only time will tell regarding the durability of immunity after a Covid-19 vaccination, it is at least as good as the immunity following infection by the virus. Moreover, decades of experience with other vaccines tell us that some vaccines provide long-lasting protection such as hepatitis A or polio, and others require boosters such as tetanus or pertussis.

The second unknown that we will gain knowledge about only with time is whether vaccinated persons can still transmit Covid-19 to others should they get infected and develop a mild illness.

In other words, apart from protective immunity that shields the individual from getting a symptomatic disease, is there sterilising immunity that prevents the individual from becoming infected at all and, therefore, unable to transmit the virus? Because we cannot guarantee this, we will still need to adopt safe distancing measures. We will still need masks, maintain our ability to detect cases early, and manage their care safely.

But we have now gained a very powerful capability. Apart from minimising severe infections, if vaccines can help us reduce the actual reproductive number for infection to fewer than one, outbreaks will fizzle out.

Here, we need only look to the example of measles, which has an intrinsic reproductive number of 15, among the highest of any infectious disease. This means one measles case in a totally susceptible population can infect 15 persons, and each of those secondary cases could infect a further 15 cases each, so that within two transmission cycles, one case could result in 225 cases.

For centuries, we were completely helpless against this virus, with thousands of children worldwide dying or going blind from measles complications every year. In 1984, the year before measles vaccination became mandatory in Singapore, there were 2,417 cases with seven deaths from measles here. Vaccination allowed us to eventually control measles outbreaks, and Singapore finally achieved measles elimination in 2018. This does not mean that there are no measles cases in Singapore, but rather, that there are no large outbreaks, nor multiple chains of transmissions.

Vaccine hesitancy 

It is understandable that there may be some vaccine hesitancy. One must acknowledge that there are some valid concerns, setting aside the wildly unscientific claims being made by anti-vaccine movements.

But we need to also appreciate why there is a pressing need for mass vaccination. Consider these figures - despite over 63 million infected globally, and more than 1.4 million dead from Covid-19 over a mere 11 months, studies using blood tests for Covid-19 antibodies indicate that less than 10 per cent of the population got infected, even in the hardest-hit countries in the first wave. That translates to at least 90 per cent of the population still at risk for catching Covid-19.

To achieve herd immunity, at least 60 per cent to 70 per cent of the population would have to get infected. If even the wealthiest nations of the world have experienced serious impact with only 5 per cent to 10 per cent of their population infected, consider the devastation and the cost in terms of human suffering which would occur by allowing the virus to burn unchecked through the population.

Vaccination provides a different path forward for humanity. But for it to succeed, we need the courage to step out, to enable Covid-19 vaccination for all who need it, and to engage patiently those who hesitate, addressing their reasonable concerns.

The world will continue to be at risk of Covid-19 resurgences, as long as the virus smoulders in any country. As our economy, society and borders are carefully reopened, vaccination serves as a protective buffer for our population.

If enough of our people are vaccinated, imported infections from visitors and returning travellers will be less likely to spark new Covid-19 outbreaks or cause serious illness. Through vaccination, we can minimise the risk of explosive spread in group settings.

Vaccines have proved successful in fighting other infectious scourges in human history. Along with other measures, Covid-19 vaccines provide hope that we will now have a powerful tool to facilitate recovery from the tremendous disruptions of this pandemic.

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.

Associate Professor Benjamin Ong is senior adviser to the director of medical services at the Ministry of Health (MOH), senior vice-president (health education and resources) at the National University of Singapore, and chairs MOH's expert committee on Covid-19 vaccination.

Singapore contributes US$5 million to COVAX, to ensure lower-income nations get Covid-19 vaccine access
Contribution to global initiative will incentivise vaccine makers to produce sufficient quantities
By Ng Keng Gene, The Straits Times, 5 Dec 2020

Singapore will contribute US$5 million (S$6.7 million) to a global initiative to ensure sufficient production of Covid-19 vaccines and access for poorer nations.

The Advance Market Commitment (AMC) is a mechanism under the Covid-19 Vaccine Global Access (Covax) Facility. It aims to incentivise manufacturers to produce sufficient quantities of Covid-19 vaccines, and to ensure access for developing countries.

In a statement yesterday, the Health and Foreign Affairs ministries said this "will help support 92 low-and lower-middle-income countries' access to Covid-19 vaccines through the Covax Facility".

AMC-eligible countries include several Asean members, as well as small states globally, they noted.

The eligible Asean countries are Cambodia, Indonesia, Laos, Myanmar, the Philippines and Vietnam.

The Covax Facility is a global risk-sharing mechanism which seeks to procure, equitably allocate and deliver two billion doses of Covid-19 vaccines by the end of next year.

It does this through supporting the research, development and manufacturing of a wide range of vaccine candidates, and negotiating their pricing.

As of Nov 25, Singapore is one of 97 self-financing participants in the facility.

The facility's implementing partners are the World Health Organisation; Gavi, the Vaccine Alliance; and the Coalition for Epidemic Preparedness Innovations.

Singapore also co-chairs the Friends of the Covax Facility group with Switzerland to support the work of the facility.

The two ministries said that the pandemic has had a significant impact on public health, society and the economy both at home and abroad.

"The virus does not respect borders, and no one is safe until everyone is safe," they said, adding that "the successful development of safe and efficacious vaccines is a critical step towards overcoming the pandemic".

They added: "Singapore will continue to work closely with our in-ternational partners, in particular, the United Nations; the World Health Organisation; Gavi, the Vaccine Alliance; and the Coalition for Epidemic Preparedness Innovations to advance vaccine multilateralism and forge a global response to this pandemic."

Choosing Singapore's Covid-19 vaccines
By Benjamin Seet and Ren Ee Chee, Published The Straits Times, 7 Dec 2020

With more than 200 potential Covid-19 vaccines being developed globally, the world is inundated each day with news on the latest developments.

How to sift through the vast amount of information, to guide the pressing decisions on which vaccines to buy or use?

To put together Singapore's Covid-19 vaccine portfolio, an expert committee reviewed more than 40 vaccine candidates over the past seven months. This involved more than a hundred meetings with companies and academics, and a detailed study of thousands of pages of scientific papers, industry reports and protocols.

Balancing a vaccine portfolio

Covid-19 fuelled the development of an unprecedented number of vaccine platforms, some of which have never before been approved for use in humans.

These include traditional and well-tested approaches using inactivated whole viruses or fragments of virus protein, newer technologies employing nucleic acids (RNA or DNA) and viral vectors (riding on another virus to deliver a payload of coronavirus RNA to the immune system).

From the outset, it was important to address multiple concerns.

This includes which technologies make better vaccines, which are safer, which will become available earlier, and which are easier to manufacture, given that billions of doses are needed to protect entire populations.

These, however, may not eventually end up as the "best-in-class" in terms of safety or efficacy.

There are also concerns of vaccine nationalism, and fears that the export of vaccines may be stopped by governments and redirected to deal with their domestic situation.

Any vaccine portfolio has to be based on robust scientific and clinical evidence, and be adequately diversified to address political and operational considerations.

Dissecting the evidence

With every company in the race presenting its own version of a vaccine, it can be challenging to choose the best.

The primary consideration is whether a particular vaccine is safe to use.

Vaccines prepare the human body to fend off a real infection, and it is not uncommon for some people to experience fever or soreness at the injection site, though they tend to recover quickly. What may be of concern are the rare cases of serious reactions caused by the vaccine or the body's immune response. Some events are so rare that tens, if not hundreds, of thousands of people need to receive the vaccine before this happens.

So there is a need to weigh the risks of infection from Covid-19 against the rare likelihood of harm from vaccination.

Another important consideration is how well the vaccine works.

One way to measure this is the potency of antibody response.

Antibodies are proteins produced by the body that target and neutralise the virus. It is generally thought that the higher the level of such "neutralising antibodies", the better the protection provided.

Vaccines also work by activating immune cells, which play different roles.

Some immune cells help with the continuous production of antibodies, leading to longer-lasting protection, while others trigger "killer cells" which seek out and destroy virus-infected cells.

A detailed study of how the immune system responds to a vaccine allows us to predict its efficacy.

Preclinical studies, conducted in a laboratory using animal models, provide us with a glimpse of how the vaccine may perform in humans. Ideally, vaccinated animals achieve "sterilising immunity", where the immune response is potent enough to get rid of the virus completely.

Vaccines that show promise proceed to human clinical trials.

In clinical trials, both safety and efficacy of the vaccine are monitored closely.

These compare outcomes in people who receive the vaccine with those who receive a placebo. At the conclusion of the trial, the vaccine group should have far fewer cases of disease compared with the placebo group.

Recent reports show that both the Pfizer-BioNTech and Moderna vaccines can achieve a protection rate of about 95 per cent, which means that most people who get vaccinated will not get Covid-19, although there is a chance that they can still pass the virus on to others.

It is also important to find out how long the protection lasts.

Many recovered Covid-19 patients continue to have antibodies in their blood even six months later.

To determine how long vaccine protection lasts, clinical trials need to continue for at least two years.

Finally, clinical trials evaluate how well a vaccine works across different age groups, particularly the elderly, as well as patients with pre-existing diseases.

Practical considerations

Beyond laboratory tests and clinical trials, there are practical issues to grapple with.

The track record of the company is important, including whether it has the resources and experience to conduct multi-centre trials across continents, involving tens of thousands of participants; and its ability to scale-up manufacturing, and distribute vaccines globally.

There are companies with vaccine candidates backed by wonderful science, but lacking the means to take them all the way to the clinic.

Some vaccines require two or more doses, while a select few claim that a single dose provides adequate protection. Others require contents from different vials to be mixed just prior to vaccination.

With the need to administer millions of doses, each additional step creates its own set of challenges.

We also need to consider logistics.

A number of vaccines are unstable at room temperature and have to be shipped and stored at temperatures as low as minus 70 deg C.

This requires the set-up of an ultra-low-temperature freezer farm to house the vaccines, and tightly coordinated milk runs to distribute them to vaccination sites.

Finally, vaccines, being biological products, have a limited shelf-life. This determines how long they can be kept if not used immediately.

Through a systematic process of expert review and evaluation, the long list of vaccine candidates has eventually been whittled down to a handful.

Singapore's final portfolio balances considerations of safety, efficacy, timeliness, accessibility and implementability, while mitigating risks of failure.

This required close scrutiny of what was published, reading between the lines of what was not, and making tough calls based on the best available evidence.

Developments over the coming months will determine whether the right choices were made.

Professor Benjamin Seet is deputy group CEO (education and research) of the National Healthcare Group (NHG) and adjunct professor at the Lee Kong Chian School of Medicine, Nanyang Technological University.

Professor Ren Ee Chee is an immunologist and principal investigator at the Singapore Immunology Network, under the Agency for Science, Technology and Research (A*Star), and adjunct associate professor at the Yong Loo Lin School of Medicine, National University of Singapore.

Both writers are members of the Ministry of Health's expert committee on Covid-19 vaccination.

COVID-19 vaccine: Will you take it? 8 in 10 say yes in Straits Times survey
But one in 10 will not consider getting vaccination, citing safety as top concern
By Joyce Teo, The Straits Times, 12 Dec 2020

A recent survey commissioned by The Straits Times of 1,000 people aged 16 and above here found that about eight in 10 would say "yes" to getting a Covid-19 vaccination, with more than half of this group willing to get it the moment it is available.

About 18 per cent of respondents, however, would not want to receive a Covid-19 vaccine, regardless of whether one was available today or in six to 12 months, although about half were willing to consider having one eventually.

With Covid-19 vaccinations under way in some countries and expected to start in Singapore soon, the question now is how open people are to the shots.

The online poll, conducted by online market research firm Milieu Insight from Dec 3 to 7, found that 48 per cent will get a vaccine when it is available, 34 per cent will wait six to 12 months, and 9 per cent will consider having one eventually.

The remaining 9 per cent said they will not get a Covid-19 jab at all.

The poll suggests that Singaporeans are far more open to Covid-19 vaccines than others in places like the United States, where recent data from the Pew Research Centre showed 60 per cent of people would definitely or probably get a vaccine for the coronavirus.

Still, this is up from 51 per cent in September, when people in the US worried that the Trump administration might rush through a vaccine before it was properly tested.

Almost a year on since the coronavirus struck, five Covid-19 vaccines have applied for emergency use authorisation.

Just this week, the United Kingdom began giving healthcare workers and elderly people the Pfizer-BioNTech vaccine (code-named BNT162b2), making it the first country in the world to authorise the shot for emergency use.

The vaccine has also since been approved for use in Canada, Bahrain and Saudi Arabia.

Some of the initial wariness about whether Covid-19 shots would be safe and effective might have come from the language used about their development. This included terms such as "warp speed" and "race", which made it sound like they were being rushed or safety guidelines were ignored, said Professor Paul Offit, director of the Vaccine Education Centre at the Children's Hospital of Philadelphia and a US Food and Drug Administration (FDA) vaccine advisory committee member.

Similarly, the ST poll found that the top concern among those hesitant about having a Covid-19 vaccine was safety, including possible side effects. Others wanted to be sure that it would be effective.

Ms V. Lee, 44, who holds a managerial post and who did not participate in the poll, said: "I will let others be the guinea pigs, and wait six months to one year."

She said she was wary, particularly after reading that two people in the UK had allergic reactions to the Pfizer-BioNTech vaccine, although the two have a history of serious allergies.

The British health authorities have warned those with a history of anaphylaxis to medicine or food not to have the jab.

Side effects, such as swelling at the injection site or low-grade fever, can occur with any vaccine.

In the Pfizer-BioNTech trial, which had more than 40,000 volunteers, the most common side effect was pain at the injection site, reported by 84 per cent of participants. This was followed by fatigue (63 per cent), headache (55 per cent), muscle pain (38 per cent), chills (32 per cent), and others.

Experts say the side effects are temporary and show that the body is building immunity against Covid-19.

On Thursday, Professor Tan Chorh Chuan, chief health scientist at Singapore's Health Ministry, told reporters that regulators typically look at two aspects of side effects - the immediate and short-lived, and the serious.

"Even after vaccination starts, as in the UK, surveillance for side effects will continue quite intensively," said Prof Tan, who is part of a 14-member vaccine advisory committee here.

Associate Professor Hsu Li Yang, vice-dean of global health and leader of the infectious diseases programme at the National University of Singapore's Saw Swee Hock School of Public Health, said the common as well as rarer adverse events associated with immediate and early-stage vaccine use would virtually all have been experienced by the participants in the Phase 3 trials, and reported.

"Delayed adverse events from vaccination are rare and difficult to prove, and are often associations due to chance rather than directly due to the vaccination per se," he said. "Unfortunately, they are also difficult to disprove, as can be seen from the long-running MMR-autism saga."

Concerns about a possible link between autism and the MMR vaccine, which protects against measles, mumps and rubella, were raised in the late 1990s, although any link was later disproved in multiple rigorous studies.

Prof Tan said Covid-19 vaccines are new, and understandably, people have concerns.

"On the other hand, we have an established process for reviewing new drugs, new vaccines. And the process has to be done stringently and thoroughly, to make sure that the things that are approved are safe and efficacious," he said.

Vaccine advisers to the US FDA voted on Thursday to recommend that the agency grant emergency use authorisation to the Pfizer-BioNTech vaccine, which has an efficacy rate of 95 per cent.

They will meet again next Thursday to discuss the Moderna vaccine (94.1 per cent efficacy), which is also pending authorisation by the European Medicines Agency.

Although the full results of the completed Phase 3 trials are not publicly available yet, they are being assessed by highly reputable regulatory agencies that will ensure that safety and efficacy criteria are met, said Prof Hsu.

Approval would indicate that a vaccine was administered safely to tens of thousands of people without any serious adverse effects.

However, in some places, vaccines are being rolled out without having been tested on a lot of people.

Russia's Sputnik V and China's Sinopharm and Sinovac Biotech vaccines have received emergency use authorisation in their respective countries despite not having completed Phase 3 trials, and are being rolled out, said Prof Hsu.

There are about 45 other Covid-19 vaccine candidates currently undergoing human trials, including one developed by Oxford University and AstraZeneca.

Prof Tan said Singapore will not rely on just one vaccine, as production would not be sufficient.

And while it is rational from the individual perspective to wait up to a year before taking a vaccine, this choice affects society at large.

"If the majority of people do this, then we end up with a tragedy of the commons from the perspective of the Covid-19 vaccination programme, because high vaccination rates are necessary for herd immunity," said Prof Hsu.

At the moment, the long-term efficacy of the vaccine front runners is unknown, but this is an issue that will become clearer only with time, said Prof Hsu.

"I think it is important for those who are hesitant to find out more about the vaccines via reliable sources of information," he said.

"They should also attempt to understand the specific issues that result in vaccine hesitancy and refusal, which may be different between persons, and make objective attempts to address these issues, including speaking with healthcare professionals."

Vaccines are not entirely risk-free, but neither is the choice of not having one in this pandemic.

The risk of becoming severely affected by Covid-19 is much higher than with a vaccine, experts noted.


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