Time to go for antigen, antibody testing

by Mohammad Didare Alam Muhsin | Published: 00:00, Jun 05,2020


A government health worker shows a COVID-19 test at the Roli Madeira riverside community in the southwest of Marajo Island, in the state of Para, Brazil, on June 1. — Agence France-Presse/Tarso Sarraf

COVID-19 pandemic devastation continues. The disease caused by the novel coronavirus, after breaking out in Wuhan in China in December 2019, has already spread to all corners of the world. In just five months it has infected more than six million people and killed nearly 400,000 people. New areas are getting affected every day. While there is no visible progress in the humiliation that the United States is now facing and the worst affected countries such as Italy and Spain have just started to recover, it started to spread with high vigour to new areas such as Brazil and Russia. The number of infection and death is also increasing in Bangladesh.

What lies behind this irresistible spread of COVID-19 at such a high speed is its extremely contagious nature. The disease spreads from one to many even before the infected people become aware of it. That is the reason almost all the countries put affected areas in lockdown to contain the pandemic so that the disease remains localised, infected individuals could be traced, isolated/quarantined and be given proper care. Many countries have already relaxed lockdown, but not before the situation came under some sort of control. Bangladesh has also reopened all sorts of activities but for educational institutions since May 31. There are reports of an increase in infection in neighbouring India after the relaxing the lockdown.

Experts fear a second wave of outbreak in other countries as well as countries that have relaxed lockdown. Against this backdrop, it is of paramount importance to analyse dispassionately what we need to do to bring the situation quickly under control. The basic strategy proposed by the World Health Organisation right from the beginning to combat the pandemic had been: ‘Test, test and test.’ This means: keep running as many tests as possible and trace each and every infected person. This is the only way we can contain the spread of COVID-19. What makes the situation complicated is that a good number of infected people, which may range from 20-80 per cent of the total infected population as the sources vary, do not show any symptoms or have just mild symptoms. It is believed that these people, while having been infected, can unknowingly transmit the disease to others even though they do not show any clinical symptoms. It is, therefore, inevitable to devise a way to trace these individuals.

It is not possible to hunt down these silent carriers merely by testing people who fall sick and show symptoms. The scope for testing needs to be increased to a much higher scale. People who are apparently healthy should also be included in the testing campaign — by contact tracing or by random sampling. This could be the only realistic approach to contain the situation. There does not seem to be any short-cut in real terms. It is assumed that the rate of infection would keep rising until it reaches a peak, after which it will get flat and remain so for a period, and then will start to taper off. Things can proceed that way only if infected individuals are rigorously tracked down through a broad-based testing campaign, and adequate and timely measures are taken to stop further transmission of infection.

An analysis of the global situation shows that countries such as South Korea, which took quick measures to identify the infected individuals through a broad-based testing campaign had a good success in containing the situation. In other countries such as the United States, the United Kingdom, Italy and Spain, which were late to respond, the infection had ample time to spread to a large extent in the community that made it difficult for them to cope with the rate of transmission even though they eventually increased the testing capacity to a much higher level.

Containing the outbreak in Bangladesh requires the government and its health managers to make continued endeavour to find a testing method that would be very quick while being highly specific and sensitive at the same time. In other pandemics, caused by other coronaviruses such as SARS/MERS, all the countries were relying on RT-PCR for testing novel coronainfection. So far, Bangladesh has also followed the same method. After the initial phase of very limited testing arrangements, it now has 52 laboratories, including those in hospitals, research organisations, universities, etc for conducting the test and they are now able to conduct more than 10,000 tests a day. However, we are yet to take any other testing method into consideration. Although RT-PCR method is highly specific and sensitive and no other method has so far been proven equally effective to identify coronavirus patients, the question remains whether we can depend on this method alone to make a massive testing campaign to trace all the infected individuals, including asymptomatic patients, at the earliest.

A quick look at America, Europe and even neighbouring India reveals that it has already been quite some time that they all have resorted to alternative methods as well. Even after making serious efforts, a highly developed country such as the United States was failing to raise the testing capacity beyond 200,000–250,000 a day while health experts are repeatedly saying that it is necessary to increase the daily testing capacity to the scale of millions to conduct a massive testing campaign before schools, businesses, churches, etc could be safely reopened.

The alternative testing methods taken into account against this backdrop are nothing new. Such methods were used earlier for viral diseases such as SARS/MERS. They identify, in samples collected from patients, antigenic proteins of virus or antibodies developed or developing in human body in response to the viral attack. Altogether, these tests are referred to as immunoassays. While RT-PCR takes several hours to complete a run, these tests could be designed to give result within 15 minutes. The tests are quite simple and easy to conduct to get the results at the point of care right at the point of time and place where the test is conducted. There is no need to send the sample to a laboratory for testing. Besides, they are quite cheap compared with the RT-PCR method that involves costly equipment, special laboratory setup and highly skilled technicians for processing samples and running the test.

Among the immunoassays, antibody testing appears more attractive because it needs just a few drops of blood as a sample that even the patient can give by a finger prick. The process of collecting nasopharyngeal swab sample for RT-PCR test not only needs a good hand but also is uncomfortable for the patient. However, an important shortcoming of antibody testing is that it does not look for the virus or any of viral components directly, but, instead, attempts to identify antibodies that develop in human body in response to the virus. In early stages of infection, when a patient’s immune response is still building up, the antibodies may not be present in detectable quantities. So, using antibody testing as the sole basis of diagnosing a current infection may not give proper results.

In contrast, antigen test is conducted on nasal/oral swab as in RT-PCR; it, however, identifies viral protein instead of its genetic material RNA. This can show a high level of specificity as seen with RT-PCR, but is relatively less sensitive. This means that if someone tests positive in such a test, it can be taken right away; but if some tests negative, it has a chance of being ‘false negative’ and there is the need for a recheck of the sample by RT-PCR if someone has overt symptoms. Now what makes the antigen test less sensitive? This happens because RT-PCR can amplify the genetic material of virus and so, it can detect it even if the viral load in the sample is small. Antigen test, on the other hand, has no such provision for amplifying the viral protein and so, it cannot identify it when the amount is too low in the sample.

‘We expect antigen tests to be less sensitive than PCR tests because the PCR tests have an amplification step that makes them able to detect very tiny quantities of viral genetic material,’ says Albert Shaw, MD, a professor of medicine at Yale School of Medicine. However, even though antigen test is inferior to RT-PCR in terms of sensitivity, the potential that it has to tremendously speed up the diagnosis has created an immense enthusiasm among experts and people in charge of health management.

Here are a few comments and reactions of some US experts and health management officials, for example. ‘There will never be the ability on a nucleic acid test to do 300 million tests a day or to test everybody before they go to work or to school,’ Dr Deborah Birx, head of the White House coronavirus task force, said in a briefing in April; ‘but there might be with the antigen test,’. When speaking on granting ‘emergency use authorisation’ for Quidel Corporation’s Sofia 2 SARS Antigen FIA, the first ever by the FDA for a COVID-19 antigen test, Dr Ashish Jha, director of the Harvard Global Health Institute, said, ‘I am very enthusiastic about antigen testing because of its ability to be scaled up to millions of tests a day, and because it has a much more rapid turnaround.’ ‘A lot of us have been looking forward to this moment’, he further says.

Former FDA chief Scott Gottlieb termed this incident ‘a real game-changer’. Although antibody testing is not useful for diagnosing current infection, it can play a vital role from a different perspective in tracking coronavirus infection and its management. By antibody testing, we can identify previously infected people, whether they had symptoms or were asymptomatic whereas the RT-PCR and antigen testing can only diagnose current infection and can give no clue about any prior infection whatsoever.

This ability of antibody testing to identify past infection could have two important implications. First, when someone develops antibodies, there could be some degree of immunity against reinfection. This can allow a person to return to work without fear. This is particularly important for physicians, nurses and other health workers who need to deal with vulnerable people and so remain in the high risk of infection. However, although the development of such immunity is true, in general, it is not still known clearly how much immunity such an individual develops and how long it could last.

‘In theory, the presence of these antibodies indicates a person has a low likelihood of being infected again,’ says Dr Tista Ghosh, an epidemiologist and medical director at healthcare company Grand Rounds in America. ‘But we do not yet know the degree of immunity or how long this immunity lasts.’ As of April, some countries were considering the issuance of ‘immunity passport’ or ‘risk-free certificates’ to people who developed antibodies so that they could travel or return to work. On April 24, the World Health Organisation reacted, by issuing a warning in a scientific brief, ‘There is currently no evidence that people who have recovered from COVID-19 and have antibodies are protected from a second infection.’

The second and probably more important implication of antibody testing is as it can identify all the people who have previously been exposed to the virus, it can be used to get a better estimate of the spread of infection in a community by conducting random antibody sampling of the general public, known as a serosurvey. This can help to get an overall picture of the spread of infection in different parts of the country, identify geographical ‘hot spots’ with higher levels of infection and accordingly pay more attention and mobilise available resources on a priority basis for ensuring adequate care. In a recent advisory issued to Indian states, the Indian Council of Medical Research says, ‘Depending upon the level of sero-prevalence of infection, appropriate public health interventions can be planned and implemented for prevention and control of the disease. Periodic sero-surveys are useful to guide the policy makers.’

This account will remain incomplete unless we indicate a potential downside of antibody testing. According to the WHO scientific brief of April 24, people infected with any one of the coronaviruses, which cause the common cold, MERS and SARS, may produce antibodies that cross-react with antibodies produced in response to infection with SARS-CoV-2, ie the novel coronavirus. This means, there is a chance of wrong identification of antibodies resulting from infection by other viruses of the corona family to give a ‘false positive’ result. There are reports saying that the world market had been plagued with so many of such faulty antibody testing kits. So, it is very important to validate any such kits for adequate specificity and sensitivity. However, Swiss pharmaceuticals company Roche has recently marketed an antibody testing kit that, as is claimed, can give a 100 per cent correct results in positive cases and 99.8 per cent in negative cases. Approval has already been granted for quite a few antibody testing kits by the US Food and Drug Administration and regulatory authorities of many other countries.

In face of the COVID-19 outbreak, various action and reaction have brought Bangladesh to a critical juncture. Having suffered the initial blow, the health system seems ready to turn around in determined steps. There has been a significant progress in testing arrangements and the management of COVID-19 patients. However, the rate of infection is constantly increasing day by day. It will be difficult to contain the situation if we cannot identify all overtly and covertly infected people quickly to stop further transmission.

By the practised RT-PCR method as is now in practice, we cannot even test people with overt symptoms while the actual need is to identify the infected people who are not showing any symptoms. So, it is urgent to decide for antigen and antibody testing to supplement RT-PCR method for widening the testing capability and include mass people in the test campaign. We need to move faster than the virus if we want to beat it. Time is flying. Indecision or delay in making decision might prove costly in the long run.


Dr Mohammad Didare Alam Muhsin is professor of pharmacy at Jahangirnagar University.

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