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It’s one of the great puzzles of the pandemic. Most developed economies are now highly vaccinated with some of the most effective shots on offer — so why are the latest COVID-19 outbreaks more deadly in some places than in others?

While it’s clear vaccines led to a drop in fatalities during the most recent delta variant-driven waves compared with earlier bouts with the virus, some countries saw deaths fall to a greater degree than others, an outcome scientists still don’t have answers for.

Countries such as Germany, Denmark and the U.K. have seen COVID-19 deaths fall to roughly a tenth of previous peaks, according to Bloomberg calculations using data compiled by Johns Hopkins University. In Israel, Greece and the U.S., fatalities fell but remained more than half of the previous peaks.

A number of countries — mostly developing economies with less capable health care systems — have relied on Chinese or Russian vaccines that have proven less effective than the messenger RNA shots used in the U.S. and throughout Europe. Those places have experienced an increase in both cases and deaths since July, when delta started wreaking havoc globally, compared with outbreaks that occurred before widespread vaccination was an option.

Bloomberg examined economies that have vaccinated more than 55% of their populations and relied on a mix of Western shots from Pfizer Inc. and BioNTech SE to AstraZeneca PLC, which have effectiveness rates of about 60% to 90% against symptomatic cases of the delta variant. One thing is clear: It’s not just the type of shots nor the extent of vaccination that counts in bringing down the death toll.

“There are a lot of factors beyond vaccinations that contribute to different outcomes across locations,” said Natalie Dean, an assistant professor of biostatistics at Emory University. “Even in places with high vaccinations, we see delta can cause a spike in cases. But do you see a strain on the health care system? And in the end I think we are seeing more variability in that outcome as well.”

To be sure, the data is a snapshot in time. There’s no guarantee that the countries where deaths have been low thus far can sustain that trend. But there are lessons to be drawn from what is the biggest and most ambitious global vaccination rollout in history.

“We’ve learned more in the last year and a half about human immunology and human vaccine responses than we probably learned in the previous several decades,” said John Wherry, director of the institute for immunology at the University of Pennsylvania’s medical school.

Dose intervals

Some of the places seeing lower death rates spaced their two shots further apart than the three-to-four week interval commonly used around the world. Controversial at the time, the U.K.’s decision in December to allow as long as 12 weeks between doses of the vaccine developed by AstraZeneca and the University of Oxford, so more people could get their first shot, has now been validated by scientific studies as providing stronger protection.

Denmark and Germany also approved longer delays between vaccinations, allowing up to 12 weeks between AstraZeneca doses in Germany and six weeks for the Pfizer-BioNTech shot in Denmark. The combined effect of two shots appears to be more potent when the second is administered after the body’s immune system has fully responded to the first shot — something that takes longer than a month.

A mass vaccination event at the London Stadium in June | BLOOMBERG
A mass vaccination event at the London Stadium in June | BLOOMBERG

“It was a natural experiment of immunology,” said Michael Osterholm, director of the Center for Infectious Disease Research and Policy at the University of Minnesota in Minneapolis, on the decisions by the U.K. and Canada to extend dose intervals. “They may have had a much more superior response because we know immunologically that people’s immune systems may be much better primed for that second dose if they wait until that whole maturation process is accomplished.”

Slow and steady

Then there’s the complex interplay of vaccination campaigns and the highly transmissible delta variant. First discovered last year in India, the variant ravaged the world’s second-most populous country through spring in the northern-hemisphere before infiltrating developed economies around mid-year.

The fastest vaccinating countries such as Israel and the U.S. — once envied for their world-leading campaigns — likely had a weaker inoculation shield by the time delta descended because of waning immunity, said experts such as Hitoshi Oshitani, an infectious disease epidemiologist at Tohoku University in Japan. Research has now confirmed that of two groups of people exposed to delta, the cohort that had been vaccinated five months earlier had a more than 50% higher rate of symptomatic breakthrough infections.

“With the waning of immunity, the earlier you started vaccination, the more breakthrough infections you have now,” said Oshitani. “This is probably why they are having high numbers of cases and deaths per population in Israel.”

In contrast, European nations that were slower to kick-start their vaccination campaigns delivered the bulk of doses only through the spring, just a few months before delta started spreading locally.

Age profile

Denmark hasn’t seen a major new wave of cases or deaths since vaccinations were started earlier this year, and the country has lifted all domestic COVID-19 restrictions. Officials say its focus on vaccinating the elderly first helped hold down the wider death toll. The peak seven-day rolling average of deaths, which never spiked above 36 in pre-vaccination waves, fell to 9% of the previous peak after vaccination.

“We were able quite early in the pandemic to contain COVID-19 disease among the elderly, especially also in the old-age care homes and also elderly citizens residing in their own houses,” said Soren Brostrom, the head of the Danish Health Authority.

A vaccination site in Luckenwalde, Germany, in February | BLOOMBERG
A vaccination site in Luckenwalde, Germany, in February | BLOOMBERG

Focusing on the elderly also helped Japan, though not to the same degree. The nation has now vaccinated around 90% of residents over the age of 65 and the effect of that was already evident when delta drove a record wave of infections in August. During that wave, the highest amount of deaths dropped 43% from the previous peak, though cases were 2.5 times higher. Given that Japan is home to the world’s oldest population, delta could have cut a deadlier swathe were it not for the prioritization of older people in its initially sluggish vaccine rollout.

“The age distribution of infections is really important to consider,” said Spencer Fox, an associate director at the University of Texas at Austin who specializes in infectious disease modeling. “For example, if children are primarily where infections are spreading in one country, but older individuals are where infections are spreading in a different country, those countries will have very different case-to-death ratios.”

Natural immunity

Japan’s summer delta surge also points to another complex, mystery factor: natural immunity in the population from previous waves. Thanks to effective containment measures, Asian countries largely avoided the worst of the pre-delta pandemic, which means they are likely more vulnerable to the highly-contagious variant — a concern underpinning the reluctance of places such as mainland China and Hong Kong to open up their borders.

At the same time, deadly pre-delta waves may have helped some highly vaccinated countries better weather the variant. South America, a region ravaged by the gamma and lambda variants earlier this year, has seen limited impact from delta, potentially due to those earlier versions creating a level of immunity, with the vaccines then acting as a booster, experts said.

Another difference is the population’s behavior, said Fox. “If unvaccinated people in one country are acting like normal, but unvaccinated people in another country are still taking large precautions, you will see very different trends.”

The U.S.’s resistance to lockdown measures and the rapid recovery of movement and travel in the first half of 2021 may have contributed to its delta death toll peaking at a higher proportion of its pre-delta level compared with European countries.

“There are lots of moving parts in all these places, and things are moving in different directions,” said David Fisman, an infectious disease doctor at the University of Toronto. “I think we’ll be able to understand in retrospect but it’s hard to figure out in real time.”

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