Friday, July 17, 2020

Eurosurveillance: 2 More SARS-COV-2 Seroprevalence Studies To Ponder


Perhaps the biggest, and arguably the most important, unanswered question regarding our COVID-19 pandemic is how protective, and how long-lasting, are the antibodies produced following natural infection (or vaccination). 

With hopes for an end to the pandemic resting largely on either `herd immunity' or (preferably) a vaccine, the question of acquired immunity is paramount.  

But even before the SARS-CoV-2 virus emerged, we'd seen limited evidence suggesting that infection by coronaviruses - including MERS-CoV and hCoVs - might not leave a durable impression on the human immune system (see 2016's  EID Journal: Antibody Response & Disease Severity In HCW MERS Survivors). 

That study famously found limited, and relatively short-lived antibody titers, particularly in those who did not have severe disease.
Over the past several months we've seen a number of other studies on SARS-CoV-2 that have produced similar results, including:

Kings College: Longitudinal Evaluation & Decline of Antibody Responses in SARS-CoV-2 infection

The Lancet: Prevalence of SARS-CoV-2 in Spain (ENE-COVID)

COVID-19: From here To Immunity (Take Two)

Nature, yesterday, published a news article :

16 July — Antiviral antibodies peter out within weeks after infection

Key antibodies that neutralize the effects of the new coronavirus fall to low levels within months of SARS-CoV-2 infection, according to the most comprehensive study yet.

However, in most people, antibody levels began to fall about a month after symptoms appeared, sometimes to nearly undetectable levels — raising questions about the durability of vaccines designed to promote the production of neutralizing antibodies.

 As I pointed out in my review of the same study last Monday:

 `. . . nAb titers aren't the only measure of potential post-infection immunity, as the role of T-Cells in fighting this virus is poorly understood.  Still, these results give pause, as it suggests many people - particularly those who had a mild first illness - may become susceptible to re-infection within months of recovery.'

Adding incrementally to our knowledge, yesterday the ECDC journal Eurosurveillance published two new studies, each of which deals with the strength and longevity of SARS-CoV-2 post-infection antibodies.  

First stop, a seroprevalence study from Germany using blood donations, that finds an unusually low number of seropositive samples, given the level of disease reported in Europe over the spring.  

It should be noted that using blood donors as a study cohort - by definition - eliminates people with a history of recent illness.  

Still, given the assumed number of mild and asymptomatic infections, the numbers reported here are unexpectedly low, which the authors suggest might be due - at least, in part - to low levels of SARS-CoV-2 IgG antibodies in some recovered cases. 

SARS-CoV-2 IgG seroprevalence in blood donors located in three different federal states, Germany, March to June 2020  
Bastian Fischer1 , Cornelius Knabbe1 , Tanja Vollmer1
Most cases of coronavirus disease 2019 are mild or asymptomatic. Therefore, many cases remain unrecorded. We determined seroprevalence of IgG antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 3,186 regular blood donors in three German federal states between 9 March and 3 June 2020. The IgG seroprevalence was 0.91% (95% confidence interval (CI): 0.58–1.24) overall, ranging from 0.66% (95% CI: 0.13–1.19) in Hesse to 1.22% (95% CI: 0.33–2.10) in Lower-Saxony.

Broad and comprehensive testing is required to better evaluate the number of people who have recovered from COVID-19 and to elucidate the magnitude of unrecorded cases. It has to be taken into consideration that not all convalescents seem to express detectable levels of anti-SARS-CoV-2 IgG antibodies and that there is missing evidence on antibody persistence. 

Moving on to the second study, researchers found that the `window of opportunity' for collecting blood from COVID-19 survivors to make convalescent plasma was relatively short, and roughly only 1 in 3 donors had a high enough antibody titer ( > 1:100) to make collection worth while.

Convalescent plasma treatment for SARS-CoV-2 infection: analysis of the first 436 donors in England, 22 April to 12 May 2020  
Heli Harvala1 , Jennifer Mehew2 , Matthew L Robb2 , Samreen Ijaz3 , Steven Dicks1,3 , Monika Patel4 , Nicholas Watkins5 , Peter Simmonds6 , Tim Brooks7 , Rachel Johnson2 , Robin Gopal4 , David J Roberts8,9 , Maria Zambon3 , the NHS Blood and Transplant Convalescent Plasma Testing Group10


Serological reactivity was analysed in plasma from 436 individuals with a history of disease compatible with COVID-19, including 256 who had been laboratory-confirmed with SARS-CoV-2 infection. Over 99% of laboratory-confirmed cases developed a measurable antibody response (254/256) and 88% harboured neutralising antibodies (226/256).
Antibody levels declined over 3 months following diagnosis, emphasising the importance of the timing of convalescent plasma collections. Binding antibody measurements can inform selection of convalescent plasma donors with high neutralising antibody levels.


Host factors and neutralising antibody levels in plasma

Neutralising antibody levels varied, with geometric mean titre (GMT) 1:333 (range < 1:10–1:2,560). Titres of 1:100 or higher, aimed for clinical use, were measured in 34% of donations (147/436). The highest levels of neutralising antibodies were found in donors hospitalised with laboratory-confirmed SARS-CoV-2 infection (data not shown, n = 22), those who were older (Figure 1A) and those who donated < 60 days from diagnosis (Figure 1C).
Consistent with the lower detection rates, there was evidence for a significant decline in neutralising antibody levels over time. Median neutralising antibody titre significantly decreased from 1:70 in those donating within 40 days from diagnosis to 1:43 and 1:22 in those donating at least 50 days (Kruskal–Wallis test; p = 0.022) or 60 days (Kruskal–Wallis test; p = 0.027) from diagnosis (Figure 1C). Similar findings were previously demonstrated in other studies on convalescent plasma donors where the proportion of high titre donors (antibody level 1:512 or above) decreased from 52% on days 31–40 post symptom onset to 28% on days 41–53 [12], and decreasing neutralising antibody levels have also been noted in SARS-CoV-2 infected hospitalised patients [17].


The study findings support the prioritisation of donation collection from only those with a laboratory-confirmed SARS-CoV-2 infection. In the study sample of 436 donations, 57 samples (13%) were negative in all three serological assays. Evidence of a laboratory-confirmed SARS-CoV-2 infection was found only for two of these seronegative donors, compared with 254 in the 379 seropositive donations (67%). With regard to the two initial laboratory-confirmed infections, subsequently testing negative by serological assay, we recognise that individuals with very mild infections may fail to develop a measurable immunoresponse.
For the 55 seronegative donors with self-reported, non-prior-laboratory-confirmed COVID-19, it is also possible that they simply did not have SARS-CoV-2 infection, given the lack of specificity of diagnosis based on symptoms only. Given the currently limited sensitivity and specificity of antibody tests for SARS-CoV-2 by conventional diagnostic standards [16-20], reporting of results to such donors needs to be undertaken very carefully and the test limitations explained.

In conclusion, most individuals with previously laboratory-diagnosed SARS-CoV-2 infection develop measurable antibody responses and also develop neutralising antibodies. A self-diagnosed infection is not a desirable selection criterion for convalescent plasma donors. Neutralising antibody levels declined within the first 3 months following diagnosis, which suggests the collection of convalescent plasma with high neutralising antibody may be optimum within a short time window. Finally, the study indicates that commercial ELISA can perform effectively as surrogate assays for predicting neutralising antibody titres and represent a streamlined and rapid way to guide convalescent plasma donor selection.

While we can't say with any certainty whether low, or declining levels of SARS-CoV-2 antibodies invites reinfection, or will negatively impact the value of a vaccine, these studies raise legitimate concerns. 

As far as the use of convalescent plasma as a therapeutic against severe COVID-19 disease - while the jury is still out and there are a number of clinical trials underway - at least one major study was recently halted after determining that hospitalized patients already had high antibody titers upon admission, more or less rendering the treatment moot.

While these studies may hint at trouble ahead on the immunity front, we really won't know until we start seeing evidence of frequent reinfection among COVID-19 survivors, or the results of vaccine efficacy trials, how much of a real-world impact they will have.