THE emergence of a new, 'highly infectious' Covid variant - responsible for more than 40 per cent of cases in the United States, where hospitalisations reached more than 40,000 a day in December - is a grim reminder that the pandemic is far from over.
This comes as concerns rise about the effects of China's reversal of its zero-Covid approach, leaving its huge population, who have little natural immunity to the virus, able to resume normal life and travel.
And here, despite most of the population having booster after booster, there are still people with Covid being treated in hospital, as the virus continues to circulate in the community.
So will we ever truly wave goodbye to this pandemic?
Locked away in a laboratory in Bangladesh is a box of white powder developed by scientists at Lancaster University that may prove a key weapon in helping us do just that.
That's because this powder, when mixed with saline, can be used as a vaccine against Covid-19. But unlike current Covid vaccines, it's not injected into your arm: it's squirted up your nose.
Crucially, whereas other vaccines reduce the risk of serious disease and death, the hope is that this one, called ViraVac, will be more successful at cutting the risk of becoming infected in the first place. It could represent a sea change in the approach to vaccination against Covid - and potentially other respiratory viruses, too.
ViraVac is based on a vaccine sprayed around barns to halt a form of coronavirus in chickens. It is one of around a dozen nasal Covid vaccines being developed.
One of these includes a two-dose nasal vaccine now being produced in India that was developed by Washington University in the US and has been approved in India as a primary vaccine and as a booster.
The vaccine was given emergency approval after studies showed that it gave "complete protection" against certain strains of Covid, after six weeks.
Elsewhere around the world, scientists have been trying to perfect their own nasal vaccines - because the more we learn about the virus, the more some believe that targeting the immune system this way is the best chance of halting the march of Covid for good.
With the standard injection, the protection varies according to the vaccine and the variant it is up against.
For instance, the Moderna booster offered an impressive 90 to 95 per cent protection against hospitalisation with a Covid-19 infection nine weeks after vaccination, according to UK Health Security Agency data released last year.
But the protection drops when it comes to catching Covid - while it offers 63 per cent protection against the BA.1 Omicron variant and 70 per cent against the BA.2 after two weeks, after 25 weeks that falls to 9 per cent protection against BA.1 and 13 per cent against BA.2.
"One of the failures of current vaccines is that they don't provide long-term protection - we rely on multiple boosters - and they don't prevent the virus being transmitted or block infection," says Lawrence Young, a professor of virology at Warwick University.
Muhammad Munir, a professor in virology and viral zoonoses at Lancaster University, believes nasal vaccines offer a solution as they "halt community transmission" - in other words, stop people getting ill with Covid and passing it on.
"It offers the chance to get a full handle on this pandemic," he says.
Central to this is the fact that nasal vaccines work on different parts of the immune system compared with vaccines given intramuscularly (i.e. as an injection typically given into the arm).
Professor Munir says that's because Covid enters the body via infected droplets that gain entry mainly through the nose or mouth, the logical approach is to focus the immunological fight there.
As he explains, vaccines given into the arm produce T-cells (which knock out infected cells) and B-cells (which produce antibodies that attack invading pathogens).
"But these immune cells are predominantly in the bloodstream and organs, with only a tiny quantity in the nose and mouth so they aren't guarding the point of entry," he says.
"And yet for Covid the route of transmission is through the nose and mouth. This area is lined by a mucus membrane that continues to the gut and is enriched with an armoury of immune cells.
"If a vaccine is inhaled or given as drops through the nose or mouth then it will prime these cells, which are the first line of defence, to act quickly."
T-cells and B-cells in the mucosal layer can prompt a lightning-fast attack "pretty much the instant the virus comes in", attacking it before it has a chance to infect cells, he says.
"These nasal immune cells get to work in a couple of minutes - whereas the immune cells made by intramuscular vaccines get to work six to eight hours after entry of the virus."
This time difference, he says, is vital. "If just one virus particle successfully sticks to one cell it takes over that cell and replicates to produce a million more viruses in an eight-hour cycle," says Prof Munir, who has been leading the research into Lancaster University's nasal vaccine.
"That's why the nasal vaccine will have the advantage - the immune cells it produces in the nasopharyngeal region can act immediately. It's a bit like having the police sitting and waiting for a crime to be committed.
"With the intramuscular vaccine approach, the police only come once the problem is there, and by that time damage could be done."
Certainly, animal studies of his nasal vaccine look promising.
A study published in the journal iScience in August 2021 found that hamsters given it had "complete protection" from lung infection and inflammation - and did not shed viral particles when infected with Covid, which suggested that it would stop onward infection.
Reducing transmission is an attractive proposition, not just to reduce cases but also because it may prevent long Covid.
Continued high transmission also leaves the door open to more variants of the virus - currently, for example, the new XBB.1.5 variant is already responsible for one in 25 cases in the UK.
"The fact that we haven't halted transmission is why we are on our tenth variant of concern," says Prof Munir.
"The emergence of this newly identified Omicron variant - which is worrying because we don't know yet how protective current vaccines will be - shows the importance of this, and there could be more around the corner."
It's not just Covid: there is a buzz in the scientific community about nasal vaccines for respiratory infections and the mucosal immunity they offer, says Professor Peter Openshaw, an immunologist at Imperial College London.
"I was at a [vaccine] conference recently where one in four presentations was arguing the importance of mucosal immunity and not systemic [i.e. body-wide] - and that's a big change."
If you can stimulate a good immune response in the mucosal layer, the immune cells in the nose can then travel around the rest of the mucosal layer down to the gut lining, adds Prof Young.
He says that this defence in the mucosal membrane in the gut against Covid especially may have unexpected benefits: "A proportion of people with long Covid have gut symptoms. And data suggests the virus can persist in the gut, so providing greater protection at the mucosal layer in the gut may help with that, too."
A nasal vaccine would also clearly be good news for needle-phobics - a 2021 study by Oxford University, which questioned 15,000 people, suggested 10 per cent of all vaccine hesitancy was linked to needle phobia, reported the journal Psychological Medicine.
"When the news was released [in 2021] that we were working on a nasal vaccine for Covid, we started getting emails from people all over the country asking if they could try it as they don't like needles," says Prof Munir. However, there are drawbacks to nasal vaccines.
"The one big advantage of injectables is you know exactly how much is being administered," says Prof Openshaw.
"With nasal vaccines you can't be so sure if some of it is sneezed out or swallowed."
A nasal flu vaccine, called Fluenz Tetra, is already being offered to children aged two and three or those with underlying health conditions aged two to 17. It contains a live but weakened form of the flu virus.
But attempts to develop nasal vaccines that are not based on weakened viruses for other respiratory infections have not yet been successful - a key problem being how to keep the inhaled vaccine in place long enough.
"The nose is lined with mucus and hair-like cells, which are good at binding to stuff and carrying it backwards into the stomach - potentially rendering a nasal vaccine useless," says Prof Openshaw.
There are other hurdles for nasal vaccines for Covid. Michael Diamond, a professor of medicine at Washington University, who helped develop the nasal vaccine that has been passed for use in India, says governments preferred to fund the development of intramuscular vaccines over others.
"We have a 50-year or more history of giving vaccines via the intramuscular route - we don't have that track record with these [nasal] vaccines," he said.
"The US government gave a lot of support to companies to work with vaccines that they thought were more likely to succeed. That consumed a lot of resources so there was not much left to support new initiatives."
After Washington University developed the nasal vaccine, a company in India (Bharat Biotech) licensed its technology and developed it.
Funding was thin on the ground in the UK, too, says Prof Munir: "There were three or four vaccine options [not nasal] on the table early on and funding for anything else dried up."
And in his case there was also a personal reason to delay work. When the pandemic broke, his young son, Ibrahim, was gravely ill in hospital with a genetic disease. With 12 years' experience working with coronaviruses, his opinion was keenly sought and he spent much time talking to other virologists while in hospital corridors - but was in no position to get into the lab.
Ibrahim died aged five in February 2020 and it wasn't until August 2020 that Prof Munir felt able to get back to work.
"My motivation was if I can't do anything to save my son, perhaps I can do something to save humanity," he says.
He and his small team set to work modifying the vaccine he originally developed for the poultry market.
"Coronaviruses wipe out the poultry industry in countries such as Egypt and Pakistan," he says.
"How we deal with these is to give them a nasal vaccine [sprayed into the air]. All coronaviruses are spread through droplets and this is the best way to stop transmission."
The vaccine is a type of viral vector vaccine. It uses a harmless virus such as a cold virus but within it is a piece of the genetic code of the Covid spike protein, which helps imitate an infection.
But whereas the one used in the Oxford/AstraZeneca vaccine was a virus that caused cold-like symptoms in chimps, this one contains a virus that affects poultry.
"And it has a receptor that sticks to the nasal tract - it's designed to develop a respiratory infection which makes it perfect to deliver a nasal vaccine," explains Prof Munir.
Modifying the original vaccine - which would be given to humans as two doses, one month apart - to be specific to Covid meant they had to ensure the portion of the spike protein they put into the virus carrier stayed put.
"We were working until 2am most days for weeks on end," he says. He recalls the "whoop whoop feeling" when the team realised the vaccine was stable even at -4C to 37C - meaning it wouldn't need expensive storage facilities, unlike the Pfizer vaccine.
"Then came the frightening part of trying it in animal studies," he says.
But, as the research with hamsters showed, it was highly effective. The vaccine is now being refined ahead of human trials due to start this year on 30,000 volunteers in Bangladesh and Peru (where they have high infection and low vaccination rates).
If successful, it could be used to vaccinate large numbers of people cheaply and quickly.
And "the know-how could then be piggy-backed to develop nasal vaccines for other contexts - even for things such as cancer", says Prof Young.
The road forward may have its twists and turns, however. Questions remain, for instance, over the length of immunity that nasal vaccines offer.
"If the lining of your nose remembered every single thing it has ever responded to, it would become overloaded, so your immunological memory there is usually of quite limited duration - which may be a necessary adaptation," says Prof Openshaw.
"This kind of immunity then tends to be short-lived."
Prof Munir says: "We won't know how long the immunity it gives lasts until it starts going up people's noses. But I believe this is going to work well."
Prof Young adds: "News of this latest variant is a wake-up call that we aren't quite out of the woods yet with Covid - and a nasal vaccine might be the answer we need now."
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