Features
Re-infections with Covid-19:
Are they distinct possibilities?
The headline of this article appeared with a different column yesterday due to a technical problem. We apologise to our readers for the inadvertent error – Editor
By Dr.B. J. C. Perera,Specialist Consultant Paediatrician
There has been considerable debate on whether reinfections implying repeated infections with the virus SARS-CoV-2 that causes the COVID-19 disease was occurring and whether such occurrences were even possible. A reinfection is a second, third or any subsequent infection with the same virus once a person has recovered from an initial index infection. Unscrambling of those contentions were obviously extremely important from public health as well as curative health perspectives. In the not too distant past, there were some suspicious cases of possible reinfections in other parts of the world but whether those were due to a persistence of the virus in the individual, reactivation of the same illness after some time in the person or whether these were due to new second infections could not be scientifically proven with certainty. Various types of conjectures and assumptions were quite rife in the face of the ambiguity of details on the topic of reinfections.
In the human health scenario, some viruses like measles or chicken pox viruses generate virtually life-long immunity and resistance to reinfections. Second infections with these viruses are extremely rare and are almost unheard of. In the other extreme, there are viruses like those that cause the common cold, with which reinfections are extremely common. There are examples of even certain other types of human coronaviruses that cause the common cold, with the propensity to cause multiple reinfections. From a public health perspective information regarding such immunological features of an infection are absolutely vital to facilitate the formulation and implementation of preventive measures.
There is now convincing evidence for at least two cases, one from Hong Kong and the other from the USA, of well-documented human reinfection with SARS-CoV-2 virus. These case reports invariably generate certain questions about how commonly reinfection may occur. The cases described here have different characteristics in terms of viral genetics, timeline of reinfection and the severity of the disease. Although we can learn quite a few things from the characteristics of these two cases, it is difficult to draw firm conclusions about the clinical and public health implications of these findings.
On August 24, researchers in Hong Kong announced the first confirmed instance of human reinfection with SARS-CoV-2. It was a 33-year-old otherwise healthy man living in Hong Kong who developed three days of respiratory symptoms and was diagnosed with COVID-19 on 26th March 2020. Following recovery, he was later PCR tested twice more for SARS-CoV-2 and both tests were negative. On 15th August 2020, he was tested for SARS-CoV-2 again as a part of re-entry screening when he returned to Hong Kong from Europe. That test result was positive. He had no symptoms at the time of the second positive result. Genome sequencing revealed that the viruses isolated in March and in August were from different genetic groups, leading the study authors to conclude that the patient had been infected twice.
In the second case, a 25-year-old otherwise healthy man living in Nevada, USA, developed a respiratory viral infection and was diagnosed with COVID-19 on 18th April 2020. The patient recovered and two PCR tests for SARS-CoV-2 performed in May were negative. Then at the end of May, the patient again developed respiratory symptoms and tested positive for SARS-CoV-2 in early June 2020. Genomic sequencing revealed that the viral isolates showed a number of genetic differences between the isolates. The authors of that report concluded that based on the degrees of genetic differences between the two isolates, these were two distinct infections.
There have also been recent news reports of one case of reinfection in Belgium and one in the Netherlands, diagnosed using genome sequencing, but the scientific details of those cases were not available at the time of writing this article.
What makes these reports of reinfection different from previous reports? There have been numerous reports of patients with possible reinfection prior to this one. In April, it was reported that hundreds of people in South Korea who had recovered from COVID-19 and were retested for SARS-CoV-2, had tested positive upon retesting. To help determine whether the patients in South Korea had indeed been reinfected and if they could transmit the virus, researchers attempted to culture SARS-CoV-2 from retest samples and traced the close contacts of those with positive retest results. The virus could not be cultured and there were no confirmed COVID-19 cases among contacts, suggesting that the detected virus was not alive. It was therefore thought that what was observed in South Korea was prolonged shedding of SARS-CoV-2, a phenomenon that is now well recognised.
The best way to establish proof of reinfection is to perform genome sequencing. The technique determines the order of chemical building blocks that comprise the genetic code of an organism. Although the genomes of different SARS-CoV-2 individual virus particles are very similar to each other and hence identified as SARS-CoV-2 and not as other viruses, some differences do occur. Those differences develop through mutations, or the substitution of one chemical building block for another, as genome copies are made. Mutations may be inherited by the next generation of virus particles, resulting in viral evolution as they accumulate over time. Genome sequencing can thus help to determine whether two populations of SARS-CoV-2 evolved separately from each other or whether one gave rise to the other. This principle can be applied to virus samples obtained from a single person at two different times.
Thousands of genome sequences of SARS-CoV-2 isolates from all over the world have been published in on-line databases. Comparison and analysis of these sequences has resulted in the characterization of several clades. A clade is a group of organisms that can be traced to a common ancestor and all common descendants. These clades of SARS-CoV-2 have geographic specificity in part because viral evolution has occurred after SARS-CoV-2 has been transported between continents. It has been found that viruses from one lineage, clade G, predominate in Europe and the United States, while clade L, the progenitor of clade G, predominates in Asia. In the case of the Hong Kong patient, genomic sequencing determined that the patient’s first infection was caused by a virus from clade V, while the second was caused by a virus from clade G. This strongly suggests that the patient was infected on two separate occasions, in different parts of the world.
Is the occurrence of reinfection surprising? The possibility of reinfection with SARS-CoV-2 has been widely argued. Several lines of evidence have been used to contend against it. Until the announcement from Hong Kong, evidence in support of reinfection had not been published. On the other hand, the occurrence of SARS-CoV2 reinfection is not surprising, based on experience with other infectious diseases. “Sterilizing immunity,” or complete protection from infection after immunologic priming by natural infection or vaccination is often an elusive target, either because short-term immunity is not fool proof or because immunity tends to wane over time. Evidence from animal studies demonstrate the possibility of SARS-CoV-2 reinfection despite immunologic priming. If reinfection is possible, why are the first cases of this are only coming up being reported now? Will there be more cases in the future? It is possible there have been other cases of reinfection that have not been detected or convincingly investigated. In essence, public health surveillance systems are not set up to identify cases of reinfection.
Based on current information, it is difficult to predict how commonly reinfection will occur, but it is useful to explore whether features of the Hong Kong and Nevada cases make those patients’ situations more or less applicable to other patients. As for timing of reinfection, it is unclear how much the time period between infections, 4.5 months in the case of the Hong Kong patient, and six weeks in the case of the Nevada patient, may have contributed to the patients’ risks for reinfection. Studies have shown that SARS-CoV-2 antibodies can decline rapidly within a few weeks or months of infection but again, the role that antibodies play in immunologic protection is unclear. It is possible these patients were poorly protected against reinfection and were reinfected as soon as they were next exposed to SARS-CoV-2. Generally speaking, immunologic protection induced by natural infection or vaccination tends to wane over time. Hence the possibility that an effective COVID-19 vaccine may need to be administered repeatedly in order to maintain sufficient immunity. It is possible that as travel restrictions ease and population movement increases, exposure to SARS-CoV-2 clades that have not been previously encountered may increase the risk of reinfection. Concerns have also been expressed as to whether immune enhancement may occur for SARS-CoV-2, and in particular, if vaccination against COVID-19 could precipitate severe disease if post-vaccination infection occurs. At this time, there is no evidence from human or animal studies that SARSCoV-2 infection can precipitate immune enhancement of the disease.
Clearly a lot more scientific information is needed before tangible conclusions can be arrived at. Our perceptions on the capabilities of this blight will change over time when more and more details and research evidence is brought to light in the course of time. However, in view of the mayhem that has so far been wreaked by the virus, time is perhaps at a premium. As time is of the essence, the onus is on dedicated researchers world-wide to unravel some of these mysteries as soon as possible.