The novel coronavirus has infected millions of people and led to tens of thousands of deaths around the globe. While it has forced almost the entire world into a lockdown, in some countries, its impact seems to be less deadly than in others.

Many observers have been left startled comparing death rates in some of the most developed economies of the world, including Europe and the United States, with those being witnessed in the much less developed countries of South Asia and Africa – where the health systems are also fragile in contrast.

According to the latest figures on the Covid-19 fatalities recorded by John Hopkins, out of the 82,992 deaths recorded worldwide, more than 41,000 have been from Italy, US and Spain combined.

Meanwhile, only 222 people have died in India and Pakistan, while no deaths have been recorded in Nigeria or Kenya.

Since its first Covid-19 case emerged on Feb 26, Pakistan has recorded 60 deaths and nearly 4,200 cases as of April 8.

A preliminary study, or an analysis as some have called it, by researchers in New York, released on medRxiv – a site for unpublished medical research – argues there may be a link between countries that mandate the bacillus Calmette-Guerin (BCG) vaccine, also known as the TB vaccine, and lower mortality and morbidity rates.

The study, which is currently being formally peer reviewed, proposes the idea by noting that in countries most affected by Covid-19, including Italy, Netherlands and the United States, the BCG vaccine is not compulsory.

It further says that in Iran, where the BCG universal policy was adopted in 1984, several people had died from the virus thus supporting the idea that the older generation, that had not been vaccinated in childhood, was deprived of the protection it offers.

The study thus concludes that countries which did not implement or had abandoned universal BCG vaccination, which mostly include western countries, had more coronavirus infections per capita and higher death rates.

In Pakistan, like in many other developing nations, the BCG vaccine is compulsory for infants. According to the government's Expanded Programme on Immunisation, since 1949, all newborns in Pakistan are given a single dose of the BCG vaccine at birth.

The BCG vaccine was first administered and then used widely after the first world war, around 1921. Other than its effectiveness in preventing tuberculosis, scientists say it also helps with other respiratory illnesses, certain bladder cancers, and could protect against asthma and autoimmune diseases such as type 1 diabetes.

After these initial findings on lower Covid-19 deaths in countries with universal BCG programmes, researchers at the University of Texas did a more comprehensive statistical study – trying to reduce the possibility of error – analysing data from 178 countries. They found that in countries with BCG vaccination programmes, the death rate was 4.28 per million while countries without such programmes faced 40 deaths per million.

But while these numbers are telling and do give hope, experts remain cautious on the potential of the BCG to provide protection. That is because these are only preliminary correlation studies at this point, and do not show a direct causal effect.

Talking to Dawn.com, Associate Professor of Paediatrics at a Karachi varsity, Dr Neel Kanth says these studies were not "evidence-based" and were only "observatory in nature". According to him, there can be a host of confounding factors that may have caused fewer deaths in these countries.

Dr Kanth says while it is true that many countries, such as Pakistan, were not witnessing high enough mortality rates compared to Italy or the US, "at this point we cannot say with certainty if the BCG vaccine programme has caused that."

"It may be true but we need to see evidence for that before being certain," he said, adding that "there could be other reasons such as an overall higher immunity rate in certain populations (which are generally more unhygienic), climate and temperature effects in those countries and several other variables. We don't know right now."

But at a time when the world is desperately searching for a way out, these observations are reason enough for many scientists to begin clinical and human trials to explore whether this vaccine can help in the crisis mankind is facing today.

They want to test whether the tuberculosis vaccine could have a similar effect against the new coronavirus, either by reducing the risk of being infected, or by limiting the severity of the symptoms.

Trials begin

France

"We have known for decades that BCG has non-specific beneficial effects", in that it protects against diseases other than the one for which it was created, Camille Locht, of the French public health research institute Inserm, told AFP.

In France, where the BCG vaccine was compulsory until 2007, "most of the study participants will have already had a first vaccination", but the protective effect of this decreases over time, said Locht.

Because healthcare workers are on the front lines of the efforts to tackle COVID-19, they should be the "first target" if there is any benefit found with the BCG vaccine, said Locht, who is finalising details for a clinical trial in France.

Netherlands

"That is exactly the reason for this research," says Mihai Netea, professor of experimental internal medicine at Radboud University in the Netherlands, which recently announced a clinical trial, with the University of Utrecht involving hundreds of healthcare workers.

This will see 500 medical professionals receive the BCG jab and 500 get a placebo.

"If during this epidemic fewer people in the BCG-vaccinated group would drop out due to illness, this would be an encouraging result," added Netea, a specialist in "trained immunity".

This is a relatively new concept based on the discovery that our innate immune response — the body's generalised defences — also has a memory, alongside the acquired immunity, which develops antibodies after coming into contact with a specific pathogen.

The BCG vaccine does not directly protect against the coronavirus, but provides a boost to the immune system which may lead to improved protection and a milder infection, Radboud university said of the study.

The idea is that the innate immune system can be prepared, or "trained" to better combat attacks, thanks in particular to live attenuated vaccines, such as BCG or measles, which contained a weakened sliver of the original pathogen.

In the case of COVID-19, in addition to infection by the virus itself, some patients have also suffered excessive immune responses, with the uncontrolled production of pro-inflammatory proteins, cytokines.

"Vaccination, in particular against BCG, might help to better orchestrate this inflammatory immune response," said Laurent Lagrost, Inserm research director who works on links between inflammation and the immune system.

The vaccine acts as a "military exercise in peacetime" so that the body can "fight the enemy effectively in wartime," he said in an interview this week with French broadcaster BFMTV.

Australia, Spain

A separate trial of the BCG vaccine has also been launched in Australia, with some 4,000 health workers, by the Murdoch Children's Research Institute.

Microbiologist Locht wants to harmonise the criteria of the French study with that planned in four Spanish hospitals, in order to better compare their results.

However, researchers in Spain, instead of using the BCG, would like to try a new tuberculosis vaccine developed by the biotech firm Biofabri.

This vaccine candidate, whose safety has already been demonstrated, should offer "better protection", said Carlos Martin, professor of microbiology at the University of Zaragoza, because it is "developed from a strain isolated in humans".

In contrast, he said the BCG is prepared from a strain of the bacteria that infects cattle, and two genes very important to the virulence of tuberculosis have been deactivated in the vaccine candidate.

Another advantage of the new vaccine is that it is made in Europe and could be quickly made available, while the BCG suffers from strong supply tensions and using it for adults against Covid-19 could deprive children of it in countries where tuberculosis remains endemic.

Germany

In Germany, the Max Planck Institute for Infectious Biology is also preparing a trial with a genetically-modified vaccine candidate, developed by the Serum Institute of India.

In coordination with these countries, Inserm announced on Thursday that clinical trials could also be launched in Africa, where health systems are expected to come under acute pressure from the coronavirus pandemic.