SYDNEY (BLOOMBERG) - Ten months ago, the results of large clinical trials appeared almost too good to be true: Two messenger RNA vaccines reduced symptomatic Covid-19 cases by more than 90 per cent in almost every group that got them.
Now, subtle differences between the Pfizer-BioNTech and Moderna vaccines are emerging across patient groups over time.
One small US study found waning levels of antibodies with Pfizer's vaccine, particularly in an older group of people. And a larger study from Belgium found that Moderna's shot may generate more antibodies than Pfizer's.
But what this all means in the real world is still unclear. While billions of doses of vaccine have been administered around the world, researchers are still working to understand the nuances of how long their protection lasts, and how it differs from one person to another.
Getting answers to those questions is a crucial step to determine who might need a booster shot, especially for older people and those with weakened immune systems.
The more-infectious Delta variant, the rise of which has coincided with slight drop-offs in vaccine effectiveness, has raised the stakes and led governments to begin rolling out a third dose of the shots.
The Food and Drug Administration will hear public arguments on Sept 17 about whether or not to go ahead with booster shots of Pfizer's vaccine. Much of the focus has been on levels of antibodies, which serve as one of the immune system's front-line defences.
One theory about Moderna's vaccine is that it creates more of those antibodies because it uses a larger dose and the two doses are administered over a one-week longer period than Pfizer's.
But antibodies are just one component of immunity, and it isn't clear if they are the most important one, especially over the long-term.
"Do we know an antibody level that protects against Covid? The simple answer is we still do not know that," said Paul Burton, Moderna's chief medical officer, in a Friday call with reporters.
Still, Moderna's trial data show that a third shot six months after the second raises antibody levels "well into that comfort zone" back above levels seen in the initial phase 3 trial.
Along with shorter-lasting antibodies, Covid-19 vaccines also trigger what's essentially a long-term memory in the immune system. That memory appears to increase and become better at making variant-fighting antibodies over time.
That longer-term protection, which includes what are known as T cells and memory B cells, is harder to measure in the lab than antibodies. But it's thought to play an important role in preventing severe illness and hospitalisations.
But less than a year into the vaccine campaign, much of the research has focused on vaccine-derived antibodies, which help lock onto an invading pathogen and tag it for attack by the rest of the immune system.
A small US study examined a group of nursing-home patients and staff who got two doses of the Pfizer vaccine. It found antibody levels in both groups waned over time.
But the 120 residents in the study, who had a median age of 76, started out with a much lower level of antibodies than the younger staff did.
Over a number of months, "they end up in an even worse spot", said David Canaday, an infectious disease physician and professor of medicine at Case Western Reserve University in Cleveland, Ohio, who led the study, which was released as a pre-print before publication in late August.
Two weeks after a second inoculation, neutralising antibodies had fallen below the level of detection in 16 per cent of nursing home residents who hadn't had Covid-19 before their immunisations.
Six months post-vaccination, 70 per cent had extremely low levels. By contrast, only 16 per cent of the 64 younger care-givers had such meagre antibodies six months out, the research found.
"Definitely the protection will drop a fair amount with these levels of antibody loss," Canaday said. But it's unlikely such a loss will mean zero protection.
A second study compared antibody levels in 167 University of Virginia health system staff immunised with either the Moderna or Pfizer vaccine.
Antibodies levels after the second vaccine were about 50 per cent higher in people who got the Moderna shot, the researchers said on Thursday in a letter in Jama Network Open.
But when the researchers dug further, they found that the difference was mostly explained by an inferior response to the Pfizer vaccine in people 50 and older, says Jeffrey Wilson, an immunologist at the University of Virginia and co-author on the study.
With the Moderna vaccine, the antibody response after two shots didn't differ dramatically by age group.
"There are probably subtle differences between Pfizer and Moderna," said Wilson. "Whether that has a clinically meaningful impact on protection against the virus remains to be seen."
The University of Virginia finding is broadly consistent with a bigger study of more than 1,600 workers at a hospital in Belgium that found people who got the Moderna vaccine had, on average, double the antibody levels of those who got Pfizer.
But the Belgian study, which was published on Monday in the Journal of the American Medical Association, found Moderna produced higher antibody levels in all age groups.
None of the studies measured whether fewer antibodies results in less protection over time. But as the Delta variant has taken over, emerging data increasingly show a deteriorating level of protection from immunisations, leading to more reports of breakthrough infections where a vaccinated person becomes ill.
Protection against severe disease and hospitalisation - the most important public-health benefit of vaccination - has generally remained strong.
"We're not seeing the hospitals filling up with vaccinated people," says Angela Rasmussen, a virologist at the Vaccine and Infectious Disease Organisation at the University of Saskatchewan in Saskatoon. "What we're seeing is mostly unvaccinated people still making up the bulk of the new cases."