Novel approaches for a novel coronavirus

SINGAPORE — Clad in overalls and equipped with N95 masks and face shields, a trio of scientists huddled over a manhole outside a foreign worker dormitory. They warned the media gathered around them last Wednesday: “Stay at least 2m away.”

When they were satisfied that we were far away enough to avoid being spattered by any stray droplets, they prized open the lid, and lowered a tube into the depths of the sewers.

They hit a few buttons on an auto-sampling machine, and minutes later, they hit pay dirt – literally.

The scientists from Singapore’s National Environment Agency’s (NEA) Environmental Health Institute were demonstrating how sewage samples for a pilot wastewater surveillance program are collected.

The samples, which are screened in a laboratory for the presence of viral material, could reveal the level of Covid-19 spread in the dormitory.

Associate Professor Ng Lee Ching, director of the Environmental Health Institute, explains: “If viral material is detected in the wastewater of some dormitories where there is no known transmission, additional swab tests for workers (there) may be arranged to identify cases for medical care and isolation.”

This sewage surveillance program is one of a slew of novel strategies that the Republic has implemented in the six months since the first Covid-19 case was reported here on Jan 23.

Human trials for a Singapore-developed vaccine will commence soon, and researchers here are studying not just the virus, but also how the human body responds to it – by scrutinizing the blood of recovered patients for clues on how the invading pathogen can be fought.

Insight examines how Singapore has engaged its best scientific minds in battling and researching the coronavirus – a foe which is still not fully understood. Says Professor Leo Yee Sin, executive director of the National Centre for Infectious Diseases (NCID): “The point is that the system needs to be flexible and scalable to cope with novel viruses that may appear in different shapes and sizes.”

On the lookout

Testing is a key enabler in Singapore’s overall efforts to fight Covid-19, says a Ministry of Health (MOH) spokesman.

This is because the speedy identification of infected patients will allow them to be quickly isolated, breaking the chain of transmission.

Traditionally, testing is done by collecting swabs from patients and running them through a procedure known as polymerase chain reaction (PCR), which detects the presence of viral genetic material in a sample.

Such tests are still the “gold standard” for testing, says MOH.

With the eventual goal of doing 40,000 tests a day, there are ongoing efforts to make this more efficient. Singapore has conducted about 177,000 swabs per million population as of July 13, the highest rate among Asean nations, according to global statistics site Worldometer.

“To allow more individuals to be analyzed in one test, we also conduct pooled PCR testing,” says the MOH spokesman. Such pooled tests involve combining swabs of up to five individuals into one laboratory test.

Where a pooled test is positive, the individuals would be retested individually to identify infections.

“Pooled testing is an effective strategy where the prevalence of infection is likely to be low,” says the MOH spokesman.

But other novel strategies, such as wastewater surveillance, are also being piloted to complement – not replace – existing testing methods.

Says NEA’s Prof Ng: “For dormitories in the program with no detected Covid-19 cases, a zero reading for the viral genetic material in the wastewater provides the added assurance that they remain free from infection and allows workers to leave for work.”

Last Wednesday, during the demonstration of how sewage samples were taken, I smelled nothing foul through the N95 mask despite the open manhole nearby.

But the murky, brown liquid collected by the auto-sampling machine was a reminder that testing can involve working in dirty conditions.

Scientifically, there were also challenges to overcome.

As Associate Professor Janelle Thompson, a principal investigator at the Nanyang Technological University’s (NTU) Singapore Centre for Environmental Life Sciences Engineering, points out: The concentration of the viral genome per liter of wastewater can be about 10,000 times less concentrated than the levels measured in human sputum (phlegm) in the first two weeks of infection.

Says Prof Thompson: “This means that methods are needed to concentrate the viral particles before recovery of the RNA (genetic material of the virus) or protein signatures used for quantification.”

Prof Thompson’s research centre had, together with other partners, provided scientific input for the methodology used to sample and test wastewater for Covid-19.

The potential of testing wastewater as an early warning system for Covid-19 was not realized in a Eureka moment.

It was derived from a strong scientific basis.

For instance, there have been a number of scientific papers that point to the presence of the virus in stool samples. This indicates that infected individuals, including those with mild or no symptoms, could shed the virus in their stool.

And then in March, Dutch researchers went one step further.

They did studies to show the correlation between the increasing circulation of the virus in the population and an increased viral load into the sewer system.

Singapore did its own tests on wastewater at water reclamation plants, which collect wastewater from all across the island, and found a similar correlation.

As of March 9, when there were 160 Covid-19 cases in Singapore, the level of viral genetic material in the wastewater was undetectable.

But in late March, when there was an increase in cases detected in foreign workers’ dormitories, levels of the viral genetic material became detectable.

A high of 1,426 new coronavirus cases was reported on April 20, most of them being foreign workers living in dormitories.

Since the beginning of this month, the number of new daily cases was less than 400.

Says NEA’s Prof Ng: “Currently, we have observed a decline in the virus signals in the water reclamation plants, and this data supports the declining numbers in reported cases and improvement of the overall Covid-19 situation in Singapore.”

The road to a cure

The number of new daily cases in Singapore may have fallen, but life has not fully returned to pre-Covid days.

There are visual reminders of this everywhere. Face masks, once emblematic of those working in healthcare, have become fashion accessories that come in various prints and colors. Large, boisterous gatherings at restaurants have dwindled to mandated groups of up to five.

The authorities say this is the way life will be – at least until a vaccine is found. There have been encouraging developments on this front.

Last Monday, the global fight against Covid-19 received a boost, with the release of encouraging findings from human trials of three coronavirus vaccines.

The results showed that the vaccines being tested did not cause any dangerous side effects, and that they could coax a protective response from the human body.

The findings were from the early phases of clinical trials for vaccines being developed by Oxford University and multinational drugmaker AstraZeneca, CanSino Biologics and China’s military research unit, and German biotech company BioNTech and US drugmaker Pfizer.

One such trial will soon also be held in Singapore. As part of a Phase I/II trial, 108 healthy individuals will receive a dose of a vaccine jointly developed by Singapore’s Duke-NUS Medical School and United States pharmaceutical company Arcturus Therapeutics.

This puts the Lunar-Cov19 vaccine with 24 other candidate vaccines around the world that are currently undergoing clinical evaluation.

But experts have pointed out that while published results from early-stage trials are encouraging, much more work is still needed to plug remaining gaps in knowledge before a vaccine can be made commercially available. Estimates for this range from 12 to 18 months.

Associate Professor David Lye, a senior consultant and director at the NCID’s infectious disease research and training office, notes that the key determinant of effectiveness of a Covid-19 vaccine lies in Phase III randomised trials, which have yet to start.

Clinical development is a three-phase process, says the US Centers for Disease Control and Prevention on its website.

In Phase I, small groups of people receive the trial vaccine, and this is expanded in Phase II to include people who have characteristics, such as age and physical health, similar to those for whom the new vaccine is intended. In Phase III, the vaccine is given to thousands of people and tested for efficacy and safety.

Six months since the first Covid-19 case was reported in Singapore, there is still no crystal ball for the future, says NCID’s Prof Leo.

“We are all charging ahead in an uncertain and rapidly evolving era, and while we aim to do our best, our best is to also rely on regional and global efforts,” she says, adding that many factors could influence how the pandemic will turn out in next six months and beyond.

But she adds: “I would like to urge all in Singapore that we keep in tune with evolution and be part of evolution, prepare to change the way we socialize and interact with one another, and play each individual part to protect self and family and the wider community.”

It will be challenging, even painful, she says, adding: “Microbes and humans are alike – we strive to survive”.

The Health Ministry says there are lessons to be learnt from countries experiencing a resurgence of cases after a general resumption of activities.

“Continued vigilance and adherence to safe management measures on everyone’s part remain important to reduce the spread of infection,” says the MOH spokesman.

“Until a vaccine is found, we will have to get used to a new normal, adjusting our routines to live and work safely despite this global pandemic.”