Three important findings from three different studies:
1. That people who survive Covid have more antibodies against Covid virus spikes than the nucleocapsid shell.
2. Monoclonal antibodies against the spike are already being developed and are progressing apace.
3. But many antibody tests are looking for the wrong antibodies.
A new study found a different pattern of antibody responses in people who recovered from Covid compared to those who died. Survivors had a antibodies predominantly against the viral spike (S), whereas early in the infection those who would not recover had more antibodies against the outer shell, known as the nucleocapsid (N). This has implications — in vaccines, testing, treatment and possibly figuring out why some people don’t even get sick at all.
Atyeo et al is a small study. But one tantalizing line suggests the pattern of antibody responses was even better at predicting who would die than the age of the patient, which was until now the best clue we had. It appears that some patients had a strong immune response but they were making more of the wrong kind of antibodies, and perhaps these would not able to neutralize, or stop the virus spreading within.
Atyeo et al looked at 22 patients to find out the difference between the immune responses of those who died and those who didn’t. Then they tested how well they could predict who would live and die in another group of 40 patients.
Vaccines that elicit a reaction to the spike will be more useful. Vaccines that don’t may even do more harm than good.
Image: Scientific Animations
On each SARS Cov2 virion there are around 100 copies of the spike but there are 1,000 copies of the nucleocapsid. So viruses may be producing ten times as much N type protein. No wonder then that some people are reacting to the N protein. The researchers wondered if it was sheer viral load that defined who would survive, but say the data suggests that it was the failure to produce S protein antibodies that was more important.
Perhaps it’s bad luck and random chance, but it may turn out that past exposure to particular coronavirus common colds (which leaves some T-cell protection) could either help or hurt the development of the right antibodies. (More T-cells soon, but not today).
Monoclonal antibodies may save the day
Ideally we could just inject the right antibodies into people and give them instant — albeit temporary — protection. But blood plasma from recovered patients is not exactly on tap and may come with “other surprises”. But there are teams working on isolating the “memory B cells” from survivors and then choosing the best so we can clone them up. These are called monoclonal antibodies, and will allow mass production of the right antibodies.
One NIH team have already picked five survivors, and isolated 252 monoclonal antibody potential lines to check. 19 of those turned out to be very useful at neutralizing the virus. Nine directly targeted the hot receptor binding domain on the end of the spike, which is probably the most useful way to stop the virus getting into human cells.
Even if we don’t get a vaccine that worked well, we can always ramp up mass production of these monoclonal antibodies. We can give these to people with weakened immune systems who couldn’t mount their own defense, and unlike a vaccine, we don’t have to wait weeks for them to develop protection. We can also give them to health workers or high risk people to prevent them getting sick in the first place. This protection may last weeks or months.
It’s just one of many tools we now have, and just another reason why I’m so optimistic that we will find a way to beat this virus sooner rather than later. It’s just a question of time.
All the restrictions and quarantines are temporary — and there are hundreds of solutions on the way.
Millions of serology tests may be looking for the wrong antibodies
Antibody tests often look for antibodies targeting the nucleocapsid, but not also the spike. Which means they may overestimate the amount of people with the healthy protective type of antibody.
In the second study (McAndrews et al) used 484 blood samples from before the pandemic, and found about 3% of healthy people who’ve never had Covid have antibodies to the coronavirus nucleocapsid, but they don’t have any antibodies to the Covid virus spike. In samples from Houston in 2020, slightly more, 3.6%, have antibodies to the nucleocapsid, but only about 1.6% have antibodies to the spike.
Abbott and Roche have together shipped over 23 million antibody tests to the US. It appears these confirm only antibodies to the N-protein, with over 200 commercial and hospital laboratory testing facilities currently using these tests. The authors warn that we need better targeted antibody tests to figure out who is immune to Covid. Though the published seroconversion studies are looking for antibodies to the spikes.
To put that in perspective, we already know that a bit under half of the population won’t get a symptomatic reaction to Covid. But we still don’t know why that’s the case or who they are in advance. This research doesn’t change the asymptomatic rate. But people testing positive to the antibody test may not have the protection that they think they have.
GEN Genetic Engineering and Biotech News
SARS-CoV-2 has two main proteins that trigger humoral immune system responses. They are the spike (S) protein and the nucleocapsid (N) protein. The N protein is produced at significantly higher levels in the virus than the S protein is, but previous studies have shown that an immune response to the N protein does not provide protection against coronaviruses related to SARS-CoV-2.
Alter’s lab compared the immune responses from the recovered individuals to those of deceased patients. They found that those who had recovered exhibited a humoral immune response that responded mostly to S protein, while deceased individuals had a shift in immunodominance such that they had a stronger immune response to the N protein.
A team headed by Chu collected samples from a cohort of 22 hospitalized SARS-CoV-2 patients, 12 of whom recovered, and 10 of whom died.
This immunodominance shift could be detected by measuring five immune response markers: IgM and IgA1 responses to S protein and antibody-dependent complement deposit, IgM, and IgA2 response to N protein. Using these five markers, researchers were able to build a model that could correctly classify clinical samples as belonging to deceased or convalesced individuals.
In order to verify this model, another 40 clinical COVID-19 samples—20 from convalesced individuals and 20 from deceased patients—from a different hospital were evaluated. The results showed the same S protein to N protein shift in immunodominance in samples from the deceased individuals, compared with those from convalesced patients.
Importantly, in the samples analyzed, this immunodominance shift was more predictive of recovery or death than were demographic factors, such as age or sex. “Thus, a minimal set of SARS-CoV-2 humoral profiles, rather than demographic information, appear to significantly resolve individuals who later went on to die from those who recover,”…
Frequently used serology test may not detect antibodies that could confirm protection against reinfection of COVID-19
Note that S-RBD means “SARSCoV-2 spike protein Receptor Binding Domain”
Results showed that 3% of healthy and non-COVID-19 samples collected during the pandemic in Houston were positive for the N-protein antibody, but only 1.6% of those had the S-RBD antibody. Of samples with the S-RBD antibody, 86% had neutralizing capacity—meaning they could prevent reinfection of COVID-19, but only 74% of samples with N-protein had neutralizing capacity. When positive for both, 96.5% exhibited neutralizing capacity.
“These findings suggest that detection of N-protein binding antibodies does not always correlate with presence of S-RBD neutralizing antibodies, and that the presence of the S-RBD antibody is the best indicator of any potential protection against reinfection,” said senior author Raghu Kalluri, M.D., Ph.D., professor and chair of Cancer Biology. “We caution against the extensive use of N-protein based serology testing for determination of potential COVID-19 immunity, and we believe that accurate and reliable S-RBD serological testing is needed to carefully identify individuals with neutralizing antibodies in order to help advance recovery efforts around the globe.”
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REFERENCES
Atyeo et al (2020) “Distinct early serological signatures track with SARS-CoV-2 survival.” Immunity Report, Published:July 30, 2020DOI:https://doi.org/10.1016/j.immuni.2020.07.020
Liu et al (2020) Potent neutralizing antibodies directed to multiple epitopes on SARS-CoV-2 spike. Nature. 2020 Jul 22. doi: 10.1038/s41586-020-2571-7. Online ahead of print. PMID: 32698192
McAndrews et al, (2020) Heterogeneous antibodies against SARS-CoV-2 spike receptor binding domain and nucleocapsid with implications on COVID-19 immunity, JCI Insight (2020). DOI: 10.1172/jci.insight.142386 [PDF]