SINGAPORE - Last June, Singapore sealed its first deal to buy Covid-19 vaccines - before any of the more than 200 vaccine candidates had even started their phase three clinical trials.
It decided not to wait for the trials, and even paid a premium on the price, in order to secure some early stock of vaccines for people here at high risk, such as healthcare workers and the elderly.
That was for the Moderna mRNA vaccine, which has yet to be approved for use here.
Singapore signed two more purchase agreements in August - with Sinovac which produces a traditional vaccine, and Pfizer-BioNTech which also uses mRNA.
These purchases should provide sufficient vaccines for the entire adult population. But Singapore is buying more.
Dr Benjamin Seet, who chaired the panel that picked the vaccines for Singapore, said several late-stage discussions are still ongoing with a handful of other companies - as part of a contingency plan should there be disruptions in the supply of purchased vaccines, delays in the delivery, or even the need for further booster shots.
Such delays have occurred with both Pfizer and AstraZeneca - which are among the handful of vaccines approved for use in some countries. And earlier this month, fire broke out at Serum Institute, India's largest vaccine facility, although the company said it would not delay production.
Singapore is known for being ultra cautious, so buying more is better, just in case.
Some of these other vaccines might also be more suitable for people who might not react well to the vaccines already purchased.
Dr Seet, who joined the National Healthcare Group (NHG) in January last year as deputy group chief executive officer in charge of education and research, was appointed chairman of the Therapeutics and Vaccines Expert Panel by the Economic Development Board three months later, on April 13.
This was shortly after the flare-up of cases in foreign worker dormitories that led to more than 54,500 infections in this group.
Dr Seet, 56, recalled: "It was around that point (when there was a big jump in cases) that we realised that the impact on Singapore could be more serious."
The decision was made that "as soon an effective vaccine was available, Singapore should get access to it", he said. "We were tasked to make sure that when Singapore needs it, we do have an effective vaccine in a timely manner."
The first vaccines were purchased two months after the panel was set up.
The panel's 18 members were picked for their wide range of expertise, and comprise experts in immunology and basic science, those with clinical experience as well as pharmaceutical company experts with experience in drug development and manufacturing.
Dr Seet himself is eminently qualified. He was executive director of the Biomedical Research Council at the Agency for Science, Technology and Research (A*Star) before joining NHG.
Even so, selecting which vaccines to put money on, early in their development process, involved hard work, a lot of reading up - "thousands and thousands of pages", said Dr Seet - and many cold calls to companies to find out more about their vaccines.
In the early days, the panel cast a wide net to include both conventional as well as novel vaccine technology by proven giants and promising upstarts.
There were about eight or nine types of vaccines being developed globally.
"We realised that it would be quite challenging to actually do a thorough review of all of them," said Dr Seet. So they whittled that down to four platforms "we thought would be more effective ultimately".
These were vaccines using RNA (not yet used in vaccines), viral vector (as in Ebola vaccine), inactivated virus (as in flu vaccines) and protein sub-units (as in whooping cough vaccine).
He explained: "We realised that we couldn't put all our eggs in one basket. So we wanted some of the old and some of the new. We also looked at it in terms of timeliness; which ones could come faster."
Even so, the shortlist had more than 40 companies.
Dr Seet said they went on the principle that "the betting average was probably about one in 10" of the vaccine candidates would make it to market.
He said "the first to the gate, we want some of that", but the team also realised that the first may not be the best. So they picked some that were likely to be fast, and some they thought would be good.
"What surprised us is that the first, indeed, could also be the best in the class," he said, referring to the 95 per cent efficacy shown by the mRNA vaccines from Moderna and Pfizer-BioNTech.
But they did not know that when they made the down payment for advance purchases of these two vaccines last year.
To decide which to put Singapore's money on, the team needed access to still confidential data to assess the potential of the various vaccine candidates.
They drew on Singapore's global network - through the Economic Development Board and Temasek's contacts as well as contacts from the scientific and medical community - to get to someone senior in those companies.
These people were in high demand. But they managed to approach, for example, Moderna's founder, Professor Robert Langer, through one of his former postdoctoral students, a returned Singaporean scholar.
Dr Seet said once they identified the right people in the company, they would make an introductory call, "to say we're interested in your vaccine, we might want to consider buying it".
Buying a vaccine that may never make it to the market was a new concept for most pharmaceutical companies, he said.
"The drug industry is probably the most regulated industry. And drug companies will sell only drugs that are fully approved."
But most of the 40-plus companies agreed. After signing non-disclosure agreements, the panel managed to talk to "the elites of the projects" such as the chief medical officers, scientists and the people who did pre-trial tests and those who ran the clinical trials.
Where necessary, colleagues from Singapore's regulator, the Health Sciences Authority, visited the production plants to check on the quality of their processes.
With the agreements, he said "it allowed us to actually have access to data before they were published".
The agreements were legal and lengthy and had to be approved by teams of lawyers from both sides, and detail how the confidential information had to be handled, who had access, and even the legal jurisdiction should there be a breach.
It usually takes up to two weeks for such an agreement, though the fastest was signed in just one day.
"As more data became available, decisions were regularly updated and refined, with new candidates added or taken off the list," he said.
By July last year, the team had narrowed the number of vaccines of interest to just over 20. This was brought down to 12 to 14 by September.
Some, such as vaccines by Merck and Australia's CSL, were discontinued by the developers.
When Singapore placed a deposit with Moderna in June, the vaccine had just entered early stage human trials. The other two purchases were also made before trial results were out.
Dr Seet said that before any decision was made, his team went "very deep into the science".
"We looked at how well-designed the pre-clinical studies were. Some gave us a lot of confidence. Some, we were a bit more wary of.
"We looked at the early data in mice, hamsters, ferrets, and for some, in primates. We looked at how strong the immune response was. We looked at different immune markers, antibody levels, T cell activity.
"We were very keen on the challenge studies where they vaccinate the animals, then expose them to the live virus to see how many actually get infected."
The team also looked at how the vaccine would be delivered. Most Covid-19 vaccines have to be reconstituted, but the panel decided against those that come as three components.
The Pfizer vaccine that Singapore is using today has to be brought in and stored at minus 70 deg C - which was not a problem for Singapore.
It comes as a suspension and has to be reconstituted with 1.8ml of saline solution injected through the vial's rubber cap. Each vial with six doses has to be gently inverted 10 times before use.
An advance purchase agreement involves several payments as milestones are reached. Should the vaccine not pan out in the end, all the money paid out goes down the drain.
On the other hand, should it prove successful, then Singapore is assured of getting some of the vaccines early.
Since deliveries are usually spread over six months or more, buying from different companies ensured an early first batch and a steady flow of vaccines.
By the end of last year, the first batch of the Pfizer-BioNTech vaccine was already in Singapore. By now, more than 100,000 people have been vaccinated.
The vaccination drive is gathering pace. The groundwork for that was laid almost a year back.
Vaccine expert panel chair a man of varied professional experience
Among the most stark and disillusioning memories Dr Benjamin Seet, 56, has from his more than three decades of work life is of flying 1,600km across the Congo - and looking down at, not forest, but hundreds of kilometres of deforestation.
Recalled Dr Seet: "It stripped away all images of the Congo that (novelist Joseph) Conrad wrote about in Heart Of Darkness, and drove home the impact man has on his environment."
The two weeks in Congo form part of Dr Seet's varied professional experience. He spent them during one of his stints with the United Nations Peacekeeping Force, which involved deployment or visits to post-conflict countries like Timor-Leste, Lebanon and Sudan. He had been seconded to the world body and held the position of chief medical officer from 2004 to 2006. Based in New York, he oversaw medical support for UN staff in 16 post-conflict countries.
But the bulk of his professional career was spent in the SAF Medical Corp. When he left after 25 years, he was its chief medical officer.
An eye doctor by training, with a master's in public health, Dr Seet then joined the Biomedical Research Council at the Agency for Science, Technology and Research (A*Star).
After eight years there, he stepped down as its executive director to join the National Healthcare Group on Jan 2 last year - only to spend much of his time from April 13 as chair of the Therapeutics and Vaccines Expert Panel. He was also involved in containing the Covid-19 outbreak in migrant worker dormitories.
Correction note: This article has been edited for accuracy.