with increasing RT-PCR Ct values
#16,050
The long-held notion that once you've been infected by a virus - and have recovered - that your body has life-long protective antibodies and you can't be reinfected by that virus, is only partially true, and only applies to some viruses.
Measles, mumps, chickenpox, and a host of other viral infection do leave lasting immunity in the vast majority of people who contract them, but exceedingly rare reinfections have been documented (see JID Clinical Reinfection with Varicella-Zoster Virus).
Viruses that are less stable, and mutate antigenically, are better able to evade prior immunity. Influenza is particularly problematic because it evolves rapidly, making it possible to catch the same subtype of influenza repeatedly over a lifetime. Durable immunity against the original infective strain, however, is assumed to remain.
In the spring of 2019, in a fascinating research study conducted by researchers at the NIH and NIAID (see C.I.D.: Influenza A Reinfection in Sequential Human Challenge), we saw that this wasn't necessarily so.
A year later, they repeated this virus challenge on the same group (n=7) with the exact same virus, expecting their residual immunity would protect them. To their surprise they found that at least 3 - and possibly 5 - of the 7 were reinfected with the exact same flu strain.
While the study cohort was small, the results led the researchers to write in their conclusion:
The data presented in this report demonstrate that sequential infection with the identical influenza A virus can occur and suggest it may not be rare. These data raise questions about immune memory responses in an acute superficial respiratory mucosal infection and their implications in development of broadly protective influenza vaccines. Further investigation of these observations is warranted.
In 2016, we looked at another problem with durable immunity - this time to MERS-CoV- in EID Journal: Antibody Response & Disease Severity In HCW MERS Survivors. This study looked at 9 Health care workers who were infected during the 2014 Jeddah outbreak (2 severe pneumonia, 3 milder pneumonia, 1 URTI, and 3 asymptomatic), and found that only those with severe pneumonia still carried detectable levels of MERS-specific antibodies 18 months later.
Those who experienced a milder pneumonia had shorter lived antibody responses (1 out to 10 months, 2 out to 3 months), while the URTI and asymptomatic cases tested negative at 3 months post infection.
Beginning last summer we began to see multiple reports of rapidly waning antibody levels in recovered COVID cases, raising concerns that between the rise of new variants, and SARS-CoV-2 infection leaving a less-than-indelible mark on the immune system, that herd immunity might be hard to achieve.
UK: Oxford Launches Human Challenge Trial To Study Immune Response To COVID-19
The Lancet: Resurgence of COVID-19 in Manaus, Brazil, Despite High Seroprevalence
EID Journal: Waning Antibody Response In Asymptomatic and Symptomatic SARS-CoV-2 Infection
Nature Medicine: Seasonal Coronavirus Protective Immunity Is Short-Lasting
EID Journal: Antibody Profiles According to Mild or Severe SARS-CoV-2 Infection
Over time it has become apparent that not everyone develops a robust, and durable antibody response following COVID infection (or vaccination). Last March, in Denmark SSI: Assessment of Protection Against Reinfection with SARS-CoV-2, we looked at the results of a large study by the SSI suggesting that protection against reinfection with COVID is far from guaranteed, particularly among the elderly.
Based on 4 million Danes who received multiple PRC tests in 2020, researchers calculated the average person is about 80% protected - at least in the short term (6 months) - against reinfection. Among those aged 65 and over, however, that protection is estimated to be only 47%.
While waning immunity over time has been identified as a risk for reinfection, we've also seen reports that some people who test positive for COVID never seroconvert, and never develop detectable antibodies.
Last summer in COVID-19: From here To Immunity (Take Two), we looked at a preprint that found Between 2 and 8.5% of infected cases failed to develop SARS-CoV-2 specific antibodies.
All of which brings us to a new Dispatch published late last week in the CDC's EID Journal, which finds an even larger (36%) portion of COVID cases (n=72) in their study failed to seroconvert. Failure to seroconvert was linked to younger age and lower SARS-CoV-2 viral loads in their respiratory tract.
Dispatch
Predictors of Nonseroconversion after SARS-CoV-2 Infection
Weimin Liu1, Ronnie M. Russell1, Frederic Bibollet-Ruche1, Ashwin N. Skelly1, Scott Sherrill-Mix1, Drew A. Freeman1, Regina Stoltz, Emily Lindemuth, Fang-Hua Lee, Sarah Sterrett, Katharine J. Bar, Nathaniel Erdmann, Sigrid Gouma, Scott E. Hensley, Thomas Ketas, Albert Cupo, Victor M. Cruz Portillo, John P. Moore, Paul D. Bieniasz, Theodora Hatziioannou, Greer Massey, Mary-Beth Minyard2, Michael S. Saag, Randall S. Davis, George M. Shaw, William J. Britt, Sixto M. Leal, Paul Goepfert, and Beatrice H. Hahn
Abstract
Not all persons recovering from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection develop SARS-CoV-2–specific antibodies. We show that nonseroconversion is associated with younger age and higher reverse transcription PCR cycle threshold values and identify SARS-CoV-2 viral loads in the nasopharynx as a major correlate of the systemic antibody response.
Coronavirus disease (COVID-19) is typically diagnosed by reverse transcription PCR (RT-PCR) amplification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA from nasopharyngeal fluids (1). RT-PCR yields cycle threshold (Ct) values that are inversely correlated with viral loads (2) and thus provide an estimate of the number of SARS-CoV-2 RNA copies in the sample. Serologic assays complement COVID-19 diagnosis by documenting past infections. In most persons, binding and neutralizing antibodies develop within 1–3 weeks after onset of symptoms (3), and titers correlate with disease severity (4).
Initial serosurveys identified antibodies in nearly 100% of persons with RT-PCR–confirmed SARS-CoV-2 infection (5). However, more recent studies have shown that seroconversion rates are surprisingly variable (6–10).For example, a multicenter study from Israel reported that 5% of participants remained seronegative despite a positive test result on a nasal swab specimen (6). In contrast, a seroprevalence study from New York found that 20% of persons with a positive RT-PCR test result did not seroconvert (8). Another study from Germany reported that 85% of confirmed infected COVID-19 contacts failed to develop antibodies (9).
To examine the reasons for these differences, we investigated the relationship between seroconversion and demographic, clinical, and laboratory data in a convenience sample of convalescent persons recruited at the University of Alabama at Birmingham (Birmingham, Alabama, USA) in 2020.
(SNIP)
ConclusionsIn summary, we show that patients with low SARS-CoV-2 viral loads in their respiratory tract are less likely to mount a systemic antibody response. Although we cannot formally exclude false-positive RT-PCR results in some participants, PCR contamination is highly unlikely as an explanation for our findings (Appendix). We also show that clinical illness does not guarantee seroconversion and that laboratories with highly sensitive RT-PCR assays are more likely to detect serologic nonresponders. These results provide an explanation for the puzzling variability of seroconversion in different cohorts.
The fact that a considerable fraction of RT-PCR positive persons fail to seroconvert has practical implications. Such persons remain undetected in seroprevalence studies, including in vaccine studies that assess protection from asymptomatic infection by measuring antibodies to antigens not included in the vaccine. Seroconverters and nonseroconverters will probably also respond differently to vaccination.Recent studies revealed that seropositive persons have a heightened antibody response after the first, but not the second, dose of an mRNA vaccine, suggesting that a single dose is sufficient (11–13; Samanovic et al., unpub. data, LINK. Serologic nonresponders might not exhibit a similarly heightened anamnestic response, but resemble SARS-CoV-2 naive persons, as was observed for 1 previously infected vaccinee who never seroconverted (14). Finally, RT-PCR positive persons who experienced COVID-19 symptoms might be less inclined to seek vaccination, believing they are protected, but our results caution against this interpretation.
Dr. Liu is a virologist at the University of Pennsylvania. His primary research interests include the evolutionary history and biology of zoonotic pathogens.
The takeaway from this dispatch is that while most people who have had a COVID infection likely seroconverted - and came away with some degree of immunity (at least against the strain or variant they were exposed to), a significant percentage likely have no detectable protective SARS-CoV-2 specific antibodies.
(Caveat: nAb titers aren't the only measure of potential post-infection immunity, as the role of T-Cells and other elements of the innate immune system in fighting this virus remain poorly understood.).
Those who believe their prior infection negates their need to be vaccinated could find out the hard way that they are less protected than they think. Granted, vaccination doesn't guarantee 100% protection either, but the more `layers of protection' you can put between you and the virus, the better your chances of are of avoiding infection in the future.
