Understanding Coronavirus (COVID-19) Infection Transmission Immunity and Testing
by Dr. C.H. Weaver M.D. 2/2021
As we approach the one-year anniversary since the outbreak of COVID-19 we have learned a great deal about SARS-CoV-2 and our ability to test for and manage COVID-19 has improved, but there remains significant disagreement about how to manage the pandemic and there is ongoing debate about how and when SARS-CoV-2 is transmitted, and what constitutes immunity.
Understanding when patients are most infectious, an individual’s duration of infectiousness, and individual immunity are of critical importance to controlling the COVID-19 pandemic.
So what do we know?
Current research suggests that respiratory spread is the dominant form of transmission and infected individuals are infectious for a relatively short period of time – less than 9 days from the onset of symptoms. Individuals are most capable of transmitting the virus to others very early, and individuals appear to mount and immune response that lasts at least 5-7 months when exposed to the virus.
How is SARS-CoV-2 transmitted?
Respiratory viruses are transmitted three main ways.
- Contact transmission – occurs when someone comes into direct contact with an infected person or touches a surface that has been contaminated.
- Droplet transmission of both large and small respiratory droplets that contain the virus can occur when an individual is near an infected person.
- Airborne transmission of smaller droplets and particles that are suspended in the air over longer distances and time than droplet transmission.
The most recent research suggests that contact transmission from a surface is unlikely to be a major route and respiratory transmission is the main route. (2)
Most respiratory virus transmission occurs from large infected droplets produced by coughing, sneezing, and breathing in close proximity to another person. This understanding has led to social distancing being the cornerstone of public health advice, but there is disagreement as to what constitutes a safe distance. The World Health Organization suggests 1 meter, or 3 feet and the CDC suggest 2 meters. For social distancing to be effective, infective respiratory particles would need to fall to the ground or be in low enough concentrations at 2 meters from the source to not cause transmission.
Airborne transmission of SARS-CoV-2 was initially thought to be unlikely but growing evidence has highlighted that infective microdroplets are small enough to remain suspended in the air and expose individuals at distances beyond 2 meters from an infected person and this may be a likely route of spread. Whether droplet or airborne transmission is the main route, the risk of infection is known to be much lower outside where ventilation is better.
How long can an infected individual transmit the virus?
In the November 2020 Lancet researchers published a meta-analyses evaluating dozens of published reports on viral load dynamics, duration of viral RNA shedding, and viable virus shedding of SARS-CoV-2. (1)
The research suggests that SARS-CoV-2 viral load appears to peak in the upper respiratory tract within the first week after symptom onset, and later in the lower respiratory tract. Individuals with SARS-CoV-2 infection are likely to be most infectious in the first week of illness. This finding is supported by the observation in contact-tracing studies that the highest risk of transmission occurs very early in the disease course (a few days before and within the first 5 days after symptom onset)
This emphasizes the importance of immediate isolation at the time of symptom onset early in the course of illness and highlights the difficulty in controlling the spread. (4-9) Patients with SARS-CoV-2 infection appear to have prolonged RNA shedding of virus up to 83 days in upper respiratory tract infection however, no live virus has been isolated from culture beyond day 9 of symptoms.
What About Immunity?
We are beginning to understand immunity to SARS-CoV-2 by tracking the re-exposure people and determining if they get sick. Initial research suggested that people who recover from even mild cases of COVID-19 do produce antibodies that are believed to protect against infection for at least 5 to 7 months, and could last much longer, (3) and that people who recovered from mild COVID-19 had memory B cells and memory T cells “with hallmarks of functionality. (3)
We now know more definitively that people who have had evidence of a prior infection with SARS-CoV-2 appear to be protected against being reinfected.(14)
In Feb 2021 researchers published new information collected from more than 3 million people who had a SARS-CoV-2 antibody test between Jan. 1 and Aug. 23, 2020. Antibody or serology tests detect serum antibodies made by the immune system proteins in response to a specific foreign substance or infectious agent, such as SARS-CoV-2.
Overall, 12% of the antibody tests were positive. About 11% of the seropositive individuals and 9.5% of the seronegative individuals later received a PCR test for SARS-CoV-2. The research team looked at what fraction of individuals subsequently had a positive PCR result at several intervals: 0-30 days, 31-60 days, 61-90 days, and >90 days which would indicate a new infection.
The researchers found that between 3% and 4% of the seronegative individuals had a positive PCR test at all intervals but among those who had originally been seropositive, the PCR test positivity rate declined over time. Initial seronegative individuals were 10 times more likely to have a positive PCR test beyond 90 days than those who were initially positive for infection.
These results suggest that having antibodies against SARS-CoV-2 is associated with protection from future infection at least for several months following an initial infection.
Initial vaccine trials have also demonstrated that vaccination produces a 4-fold increase in antibodies to SARS-CoV-2 one month after vaccination and a T-cell response in all participants that peaked by day 14 and was maintained 2 months after vaccination. The vaccine elicited neutralizing antibody responses against SARS-CoV-2 in 91% of study participants 1 month after vaccination and in 100% of participants after receiving a second dose.
IgM-IgG Antibodies Against COVID-19
Identifying antibodies to the coronavirus (SARS-CoV-2) in an individuals bloodstream can be used to determine whether a person previously had COVID-19. The test is most useful for policy makers and scientists for tracking the pandemic. This test cannot determine if you have an active infection, determine if you are infectious to other people, or confirm immunity to re-infection with certainty. Having this test does not change recommendations for social distancing, hand washing, no-face-touches, surface disinfection, etc.
Your bodies immune system makes IgG and IgM antibodies that can be detected it the blood and provide useful information about an individuals past exposure to the virus but not much is known about immunity. This is not a test to detect active infections, it looks for antibodies after an individual has had an infection. In fact the sensitivity of antibody testing is poor until at least 3-4 weeks after the initial infection. A positive result means that one has been exposed to and has developed an immune response to the SARS-CoV-2 virus. Both IgM and IgG antibodies are created gradually over the course of 1-2 months
- IgM stays positive for ~ 6 months or longer.
- IgG is usually associated with immunity and could stay positive for 2 years or longer (based on old SARS-CoV-1 coronavirus studies)
Does IgG or IgM Predict Immunity?
Although serological assays to detect SARS-CoV-2 IgG and IgM antibodies are available it is presently premature to use such assays to determine whether individuals are immune to reinfection.
Understanding whether and how recovery from a COVID-19 infection confers immunity to or decreases the severity of reinfection is needed to inform current efforts to safely scale back population-based interventions, such as physical distancing. Following infection with COVID-19, detectable IgM and IgG antibodies develop within days to weeks of symptom onset in most infected individuals. It remains to be determined however whether a robust IgG response corresponds with immunity. Well-designed longitudinal studies of persons who recovered from COVID-19 are needed to monitor for signs and symptoms of recurrent illness.
The potential for cross-reactivity with other coronaviruses (yielding false-positives) have yet to be determined. Widespread testing of persons who have not had COVID-19, a population with low SARS-CoV-2 prevalence, can generate more false-positives than true-positives. We do currently know however that
- Two cases of SARS-CoV-2 reinfection have now been confirmed.
- There is also no evidence that individuals infected with SARS-CoV-2 have transmitted the virus to others after they had clinically recovered. However, this possibility of transmission cannot be ruled out.
World's First Confirmed Cases of COVID-19 Reinfection Reported
A reportedly young and healthy patient was documented to be infected with COVID-19 4.5 months after the first infection according to doctors at the University of Hong Kong. The patient is a 33-year-old man in Hong Kong who had mild symptoms the first time he was infected, and no symptoms the second time. The researchers said his reinfection was discovered after he returned from a trip to Spain, and the strain he had closely matched one circulating in Europe in July and August.
Several cases of suspected reinfection have been seen in the United States and elsewhere, but until this week none were confirmed. A second man in Nevada has also been reported to have been infected with COVID-19 for a second time. Evidence of reinfection is a cause for concern because it suggests that immunity to the new coronavirus may last only a few months in some people.
It’s important to understand however that there is a “spectrum of immunity” that ranges from complete immunity to very short durations of immunity. Once someone recovers from a novel coronavirus infection, are immune from the virus at some level but the strength of the immunity and its duration are unclear. The two recently reported cases from Hong Kong and Nevada suggest that immunity is not absolute, and people previously thought to be immune can get a second COVID-19 infection.
Individuals exposed to the virus do have an increase in their antibody levels however the strength of their immunity appears to be related to the severity of their initial infection. People who have a mild or asymptomatic infections may have a lower immunity level as evidenced by lower levels of antibodies that can be detected.
In summary, existing limited data on antibody responses to SARS-CoV-2 and related coronaviruses, as well as one small animal model study, suggest that recovery from COVID-19 might confer immunity against reinfection, at least temporarily. However, the immune response to COVID-19 is not yet fully understood and definitive data on post infection immunity are lacking. (1)
Like other serological, or antibody-based, diagnostic assays, it uses an enzyme-linked immunosorbent assay (ELISA), which employs a portion of the target virus to find antibodies. Although serological tests are not useful for quickly identifying whether a patient currently has COVID-19 the help researchers understand how humans produce antibodies to the virus. Serological tests can also help determine if a person has been infected whether or not the individual had symptoms—something an RNA test kit cannot do after the fact, because it only looks for the virus itself. That means serological tests could be used to survey a population to determine how widespread infection rates.
How Do Doctors Test for COVID-19 Infection?
Until August 2020 the main way people were tested for COVID-19 was to place a sterile swab at the back of a patient’s nasal passage, where it connects to the throat via the nasopharynx, for several seconds to absorb secretions. After a sample is collected, the swab goes into a liquid-filled tube for transport.
To determine whether a nasopharyngeal sample is positive for the coronavirus, biotechnicians use a technique known as reverse transcriptase polymerase chain reaction, or RT-PCR. To perform this test a technician extracts viral genetic material called RNA (if it is present) from the sample and uses it to produce a complimentary strand of DNA that the RT-PCR technique amplifies, or makes thousands of copies of, to get a measurable result. The primary difference from one kit to another is which coronavirus genes each test targets.
FDA Authorizes COVID-19 Tests for Self-Testing at Home
First OTC Rapid Antigen Test; The Food and Drug Administration granted authorization to Ellume for its COVID-19 Home Test December 19th, 2020. This is the first over the counter (OTC) at-home diagnostic antigen test for coronavirus disease 2019 (COVID-19). The test will cost $30 and is designed to detect active COVID-19 in individuals aged 2 years and older with or without symptoms.
The test kit nasal swab, a dropper, processing fluid, and a Bluetooth® connected analyzer for use with an app on a smartphone; step-by-step video instructions on the app aid the user in performing the test. Real-time test results are then transmitted to the user’s smartphone in less than 15 minutes and can be shared with health care professionals, employers and schools.
In a simulated home-setting clinical study which included 198 individuals aged 2 to 82 years. the Ellume COVID-19 Home Test achieved 96% accuracy, with an overall sensitivity of 95% (positive percent agreement) and a specificity of 97% (negative percent agreement) when compared to an RT-PCR laboratory test.
Although highly accurate the test is a little less sensitive and less specific than PCR tests run in a lab. Its value is that it can be used completely at home and return results quickly. The FDA noted that there is a small percentage of positive and negative results that may be false with this test. Positive results in asymptomatic individuals should be treated as presumptively positive until confirmed by another test as soon as possible.
FDA Authorizes First Combination COVID-19, Flu for Home Use
The FDA announced it authorized the first combination test that allows patients to collect saliva samples at home and have them analyzed at a laboratory for the presence of COVID-19, influenza A and influenza B.
Quest Diagnostics makes the RC COVID-19 +Flu which is intended for those with a respiratory viral infection “consistent with COVID-19” and for whom home collection is “determined to be appropriate” by a health care provider. Quest Diagnostics indicated that it takes approximately 2 to 3 days for all patients and 2 days for “priority patients” (eg, hospitalized patients) to receive antibody and molecular diagnostic test results.
Interpreting Test Results
When the test is positive it provides “actionable” information. If you have a positive test we consider a person infected and potentially contagious. A negative test is harder to interpret.
It is essential to understand that a negative test does not rule out COVID-19 infection. It is currently estimated that the COVID-19 test is falsely negative 15% to 50% of the time. When diagnostic testing is negative, the possibility of a false negative result must be considered in the context of a patient’s recent exposures and the presence of clinical signs and symptoms consistent with COVID-19.
There are a number of reasons a test might be negative when a person is sick with the coronavirus.
- It might be too early in the illness, when the amount of virus in the airway is still small.
- It could be a problem with how the swab was done.
- Swab collection techniques; the back of the nose, the throat, the outer nose have different levels of accuracy.
- Issues with the handling or transport of the swab. There could be laboratory error.
- The test is also only true for a single point in time. A person who sought testing for symptoms caused by another pathogen could easily contract the coronavirus in the time between being swabbed and receiving the result. Or if they are early in the illness, they might test negative because the virus hadn’t multiplied enough.
Some Who Tested Negative Have Tested Positive Again
There is currently an increase in “second-time” infections in Wuhan, further calling into question the accuracy of COVID-19 diagnostic testing as China prepares to lift quarantine measures that would allow residents to leave the city. It's also raising concerns of a possible second wave of cases which in the case of the 1918 pandemic proved to more fatal than the first wave.
From March 18-22, the Chinese city of Wuhan reported no new cases of the virus through domestic transmission, but some Wuhan residents who had tested positive earlier and then recovered from the disease are testing positive for the virus a second time. It has been reported that as many as 15% of individuals testing negative on two occasions subsequently tested positive again 2-3 weeks later.
It is unknown if those who retested positive are asymptomatic carriers or are infected again. Asymptomatic carriers are infectious but do not exhibit any of the illness's associated symptoms. On the other hand, could a second positive test mean a second round of infection? Most experts believe it is unlikely that a COVID-19 patient could be re-infected so quickly after recovery, but it is too soon to know for certain.
Other Testing Techniques
Novel Rapid Tests: Abbott labs is releasing their recently approved coronavirus test that is reported to be able to tell if someone is infected with COVID-19 in as little as five minutes. The new Abbott ID NOW COVID-19 test runs on Abbott's ID NOWTM platform which is a small ~ 6 pound box that can sit in a variety of locations allowing testing to be quickly performed at the point of care. Similar tests will be released by other companies as well.
The test still relies on correctly taking a swab from the nose or the back of the throat, then mixing it with a chemical solution that breaks open the virus and releases its RNA which is then amplified and measured by the device. The test will be helpful for more rapidly identifying infected individuals based on a positive test. This is especially useful for health care workers and first responders who test positive, so they don't place others at risk. Given that the sample obtained for test is identical to that used for currently available tests the false negative rate is unlikely to be any better than the other available tests so negative test results carry the same problem of not providing a high level of certainty that one is not infected. It also could allow public health agencies to figure out who is already immune to COVID-19
Lastly, remember that over testing drains sorely needed personal protective equipment that health care providers need to perform their vital functions during the pandemic. Testing should not be routinely performed on all individuals and reserved for those with symptoms consistent with an active infection.
So How Do Medical Tests Work?
Any medical test has two important qualities: sensitivity and specificity. In the case of the Coronavirus tests are proven to be “sensitive” by detecting the smallest amount of virus. The tests must also be “specific” ensuring they do not mistake other pathogens, such as influenza or rhinovirus for the new SARS-CoV-2. When developing a test, researchers typically make some trade-offs between sensitivity and specificity – in other words it’s almost impossible to be 100% sensitive and specific.
First and foremost it’s important to understand that no test evaluating the COVID-19 virus will be 100% accurate. Some test results incorrectly determine that a person is infected when they are not – these are called “false positive” tests. Some tests determine that someone doesn’t have the virus infection, but they do. These are called “false negative” test results. While false positive tests are disconcerting to the individual, it’s the false negative results for COVID-19 that are the main problem for managing the pandemic.
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- FDA press release, August 17, 2020; STAT, August 17, 2020; Vogels, CBF, Brackney D, Wang J, et al. SalivaDirect: Simple and sensitive molecular diagnostic test for SARS-CoV-2 surveillance. medRxiv preprint. August 4, 2020.
- Coronavirus (COVID-19) update: FDA authorizes antigen test as first over-the-counter fully at-home diagnostic test for COVID-19. [press release]. Silver Spring, MD: U.S. Food and Drug Administration; December 15, 2020.
- FDA authorizes Ellume COVID-19 Home Test as first over-the-counter fully at-home diagnostic test. [press release]. Valencia, CA and Brisbane, Australia: Ellume; December 15, 2020
Viral Kinetics and Antibody Responses in Patients with COVID-19
medRxiv - The Preprint Server for Health Sciences