Still a mystery

With herd immunity an open question, vaccine trials still ongoing and repeat outbreaks in countries that opened up, continuing to wear masks, practising physical distancing and minimising crowd situations may be the only way to keep the virus at bay.

Near Piccadilly Circus in London on June 15. Being cautious with COVID-19 is the best strategy for survival.

BOTH COVID-19 and lockdowns are equally depressing. Hope is unique to humans and it is infinite. Tired of lockdowns, hotspots of infection and reports of escalating cases worldwide, the world is eagerly awaiting either of the two magic bullets needed to get past the COVID-19 pandemic: herd immunity or vaccines. Are we there yet? The answer is a resounding “No”. Diseases such as measles and chickenpox, once common among children, are now rare even in the least developed countries. Thanks to vaccines and childhood infections, there is enough herd immunity to contain large outbreaks from these old challenges. So, we remain hopeful.

The concept of herd immunity is not new. It means the “majority” of the population has been exposed to a virus and survived. In such a scenario, when the virus enters the body, the antibodies (the fighter proteins in the blood, equipped with a detailed memory of the invading virus) make it difficult for the virus to invade the body. How do antibodies help? Like water on fire, they can easily go to and neutralise the invaders. Early on in the outbreak of COVID-19, we heard that its R0 value, or the basic reproductive number, was between 2 and 5. This means that in normal settings where everyone is susceptible, an infected family member can give the infection to two to five family members. But if three out of four people have had previous infections and thus have antibodies with a good memory of SARS-CoV-2, the virus that causes COVID-19, then the newly infected family member cannot infect the three family members who had the disease previously and can cause only one infection. And that makes it much less likely that large clusters of COVID-19 can flourish, and infection transmission dies out.

So, what does the “majority” of the population mean in real numbers in terms of exposure to COVID-19 to achieve herd immunity? The threshold for herd immunity to SARS-CoV-2 is unknown. “Guesstimates” range between 60 and 80 per cent. For most known diseases, the conventional number is 80 per cent, meaning 80 per cent of the population has been infected and survived because of immunity or resistance to the disease. For other diseases, herd immunity is achieved with vaccines to a level of 95 per cent. In other words, if 5 per cent of the population remains susceptible to the diseases, they are so few in number that they are unable to cause widespread disease. We still see outbreaks of diseases such as measles, but they are usually confined to a small percentage of the unvaccinated population. A lower level of exposure to the disease, say 7 per cent for COVID-19 in Sweden currently, in the population can still slow the spread of a disease somewhat, meaning that this 7 per cent will not play role in transmission. But that will not be sufficient to reduce the R0 value. The herd immunity number represents the point at which infections are substantially less likely to turn into large outbreaks.

Five questions about herd immunity remain to be ascertained. First, does the presence of antibodies really lead to immunity (or are these antibodies really able to neutralise new invading viruses)? Second, how long will immunity last in an individual? Third, can we get to the required percentage at the population level? Fourth, are adequate types of tests available to realistically measure the concept of herd immunity? Finally, will herd immunity requirements vary in populations depending on socio-economics, density, age and pre-existing diseases.

We do not know the answers to the first two questions. On the third question, data from some of the hardest-hit cities in the world suggest that the vast majority of people still remain vulnerable to the virus. The percentage of people with antibodies remains very low. This is true for communities that underwent lockdowns such as New York City (20 per cent) and Wuhan (10 per cent), for those that did not implement drastic measures such as Sweden (7 per cent) and for those that considered delaying lockdowns hoping to achieve natural immunity such as London (18 per cent).

All the other hotspots have a lower prevalence of antibodies (Madrid, 11 per cent; Boston, 10 per cent; and Barcelona, 7 per cent). On the basis of these numbers, it can be easily said that 7-10 times as many people need to get infected to reach the desirable 60 per cent-80 per cent range of illness in the population so that there is sufficient immunity in populations and outbreaks will not occur.

What we do not have are populations where no mitigation was implemented, like a lottery, knowingly letting many people die for the benefit of a few winners. This was done to 399 poor black men with syphilis in Tuskegee, Alabama, United States, starting in the 1930s. The men were denied treatment so that the progression of the disease could be observed. In 1994, U.S. President Bill Clinton apologised to the victims of this experiment, and this led to significant oversight for all scientific studies done now. Today, we are unlikely to get such data anywhere in the world.

The single-digit numbers of prevalence of COVID-19 antibodies quoted here are a fraction of the ideal numbers required to reach a level at which the virus can no longer spread widely. It would be inhuman to let the virus run rampant in a population to achieve this level of immunity in the natural state. Simply put, we do not have a good way to safely build up immunity.

Serology surveys

The tests required to assess herd immunity are different from those that help with the diagnosis of the disease. To assess immunity, we need tests that look for antibodies in people’s blood, the proteins produced by the immune system that indicate a past infection. People who had no symptoms would be recognised via these types of antibody tests. However, these tests are far from perfect. And may sometimes be wrong. Some other viruses may have similar features to SARS-CoV-2 (such as the first severe acute respiratory syndrome (SARS) virus of 2003 or other coronaviruses). In New York, studies were conducted among people going to supermarkets. In Wuhan, studies were conducted among people in hospitals. These do not represent the whole population. In other cities, serology surveys are finding much smaller shares of people with antibodies. Even in hotspots with declining or flattened curves, the current waves of infection may have only infected the super-vulnerable, and many population groups may not yet have been exposed to the virus. Therefore, what is needed are studies that use these tests to examine a cross section of a population, giving equal opportunity for all segments of the population (rich and poor, old and young, good and bad neighbourhoods) as was done for AIDS. These are called serology surveys and take time to conduct.

Variations in herd immunity will take time to study. For example, in crowded situations such as pilgrimage sites and sports events or movie theatres, one infected person would remain in close proximity to multiple contacts for extended periods of time as opposed to an infected person passing a fellow walker on the street for a few seconds. A hospital waiting room with a mix of people with diabetes and hypertension is different from an airport waiting room.

Putting together the currently available data and lack of evidence on additional factors, herd immunity protection is unlikely to be a reasonable option in the near future.

Vaccine front runners

Therefore, the second and only hope is a vaccine. Many promising vaccines are undergoing trials. There are 26 front runners (https://www.the-scientist.com/news-opinion/covid-19-vaccine-frontrunners-67382) and numerous others listed on the clinical trials website, which is a repository of all trials (https://clinicaltrials.gov/ct2/who_table). Over 100 treatment options are also listed in the clinical trials list.

Vaccines will require time to pass through preclinical development (mostly in laboratories) to the human trials phases: phase I (safety in humans), phase II (activity against artificial infection in humans) and phase III (safety and efficacy in natural conditions in humans). This will take at least 8-12 months if all goes well. What is seen as promising in laboratory test tubes, often the focus of media attention, may not always work in a human being. Only about one out of 10 candidates from the preclinical stage will reach final approvals. There may be diseases and medications that challenge the outcome of such studies.

Making vaccines available globally is another challenge, and post-marketing surveillance will still need to be done. Vaccine hesitancy (people refusing vaccines for a variety of reasons: a disbelief in vaccines, trust in natural immunity, religious reasons, conspiracy theories against vaccines) remains a challenge to many vaccine programmes, which has led to sporadic global outbreaks of diseases such as polio and measles. There is as yet no vaccine for the coronavirus, so getting to herd immunity without a new and effective treatment could mean many more infections and many more deaths.

True, there are many diseases without a vaccine or cure. But a lot is known about them. COVID-19 is a new disease. There are about 7.5 billion people in the world. Even if the possibility of death from COVID-19 is 1 per cent, that still means a large number of deaths. As in war situations, a successful outcome is tied to our ability to predict the behaviour of the enemy, to evade the enemy and, finally, to conquer the enemy. For now, we do not know what direction this virus is taking. Countries that opened up after successfully controlling the first wave, including Singapore, China, Japan and South Korea, have all experienced repeat outbreaks. While we should rejoice in any pause in outbreaks, that should not lead to complacency. Therefore, being cautious with COVID-19 would be the best stratsegy for survival. Being cautious means universal face covering, physical distancing and minimising crowding situations. These are not magic bullets, but together, they can help.

Shahul Hameed Ebrahim, MD, MSc, PhD, is an American medical epidemiologist of Indian descent affiliated with the University of Sciences, Techniques and Technology of Bamako, Mali. He has advised governments on pandemic mitigation—the 2009 influenza pandemic, the Middle East respiratory syndrome in Saudi Arabia and the Ebola outbreaks in Congo (2012) and in West Africa (2014-15)—and authored over 80 scientific papers, including on COVID-19.

N.M. Mujeeb Rahman, MBBS, MS, is a former medical superintendent of MES Medical College, Malappuram, Kerala, and director and consultant surgeon at Nizar Hospital, Malappuram, and is a member of an international coalition of COVID-19 researchers advancing multi-country studies on mitigation.