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I was confused about that as well. The article suggests that targeting "other portions of the spike protein" (as immune systems previously infected with COVID d

I was confused about that as well. The article suggests that targeting "other portions of the spike protein" (as immune systems previously infected with COVID do) results in the immune system being _less_ robust against variants of the virus than targeting "places on the RBD" (as immune systems exposed to Moderna's mRNA vaccine do): > Specifically, antibodies elicited by the mRNA vaccine were more focused to the RBD compared to antibodies elicited by an infection, which more often targeted other portions of the spike protein. Importantly, the vaccine-elicited antibodies targeted a broader range of places on the RBD than those elicited by natural infection. > These findings suggest that natural immunity and vaccine-generated immunity to SARS-CoV-2 will differ in how they recognize new viral variants. What’s more, antibodies acquired with the help of a vaccine may be more likely to target new SARS-CoV-2 variants potently, even when the variants carry new mutations in the RBD. Anyone with more experience in immunology care to weigh in on why the second paragraph there follows from the first? Naively, one might expect targeting a wider variety of places on on the COVID spike protein to result in better immunity against variants, not worse. Why is the article saying the opposite?

rolph 5y ago
when you target many epitopes, you are shooting at the 10 inch ring; target one epitope of critical function [put one in center of mass] you are shooting the 2 inch ring. immune systems dont look at everything at once, they find something that sticks and and over trials sharpen the response until highest efficacy of antibody epitope combination is found. the vaccine is like a laser guided munition, natural immunity is like carpet cluster bombing; both highly effective but in different modalities.
bena 5y ago
The way I read it is that vaccine immunity is engineered towards COVID in general. It'll catch variants because they're still COVID. Natural immunity knows only of COVID-19 Alpha. But it knows it well. All those nooks and crannies the other variants may not have, the natural antibodies can latch on to.
rcxdude 5y ago
I think it's because the other parts of the virus are more likely to change over time, because there's lots of neutral mutations available: changes which don't affect fitness but do affect antibody response. The RBD by contrast is much more constrained: most mutations there result in a virus which can no longer infect cells, so it's much less likely to change (though of course any mutations which increase its effectiveness will be heavily selected for). This I think was one of the main reasons the spike protein was targeted by the mRNA viruses.
criticaltinker 5y ago
> Why is the article saying the opposite? The cited study in OP may have a slightly pro-vaccine bias, potentially because two authors have "the potential to receive a share of IP revenue" on a relevant patent, and because one author consults for Moderna. Regardless, the study presents scientifically accurate findings, but in a few places it tries to stretch those into questionable conclusions. For example, the authors write: > At first glance, the RBD targeting of the vaccine sera neutralization might seem likely to increase susceptibility to viral mutations, but the rest of our results suggest that this MAY not be the case. [4] So keep that tilt in mind when reading it. > one might expect targeting a wider variety of places on on the COVID spike protein to result in better immunity against variants Yes this is good intuition, here are excerpts from other literature illustrating why targeting a wide variety of SARS-COV-2 proteins can provide better immunity. In fact, this reasoning is why ongoing vaccine research is investigating formulations beyond the current solely spike protein focused vaccines. Notably, one shortcoming of the current mRNA vaccine formulations is that they do not induce nucleocapsid (N) protein antibodies - whereas natural infection does. > The nucleocapsid protein of SARS-CoV-2 has been suggested to be an important target for T cell responses. [1] > Firstly, this protein contains conserved cross-reactive T cell epitopes that are present among different coronaviruses, suggesting that it could be an ideal target for universal coronavirus vaccines. [1] > Secondly, the nucleocapsid protein is among the most abundant structural proteins in the coronavirus lifecycle, which may facilitate early antigen presentation and recognition by T cells. [1] > Previous knowledge on other related coronaviruses and the prompt sequencing of the SARS-CoV-2 genome early in the pandemic allowed to identify the spike (S) and the nucleocapsid (N) structural proteins as major targets of antibodies. [2] > The surface glycoprotein S, which contains the receptor-binding domain (RBD), has a better known function in immunity and is the leading antigen candidate for vaccine development. N is smaller than S, lacks a glycosylation site, and is extensively used in leading serodiagnostics kits due to its abundant expression during infection and early antibody response but its immunological relevance is less established. [2] > N forms ribonucleoprotein complexes during the virion assembly process by binding to the viral RNA genome and packing it into long helical structures. Its main function is to regulate viral RNA transcription during replication, promoting the synthesis of its own proteins while interfering with the metabolism, protein translation, and proliferation of the infected host cell. During the process of infection, N dissociates itself from the genome and is exposed to the host immune system, and its high immunogenicity has also prompted its exploration as vaccine target. [2] > Interestingly, significant protein similarity between SARS-CoV-1, SARS-CoV-2, and other HCoV has been reported for N, including a highly conserved motif in the N-terminal (NT) half of the protein (FYYLGTGP) and relevant immunodominant epitope regions. [2] > Evidence from multiple experimental studies showing that single RBD point mutations can lead to resistance to neutralizing convalescent plasma from multiple donors suggests that specific single mutants may be able to evade spike-targeting vaccinal immunity in many individuals and rapidly lead to spread of vaccine-resistant SARS-CoV-2. [3] [1] Combining spike- and nucleocapsid-based vaccines improves distal control of SARS-CoV-2 https://www.cell.com/cell-reports/pdf/S2211-1247(21)01108-6.pdf https://www.cell.com/cell-reports/pdf/S2211-1247(21)01108-6.... [2] Immunogenicity and crossreactivity of antibodies to the nucleocapsid protein of SARS-CoV-2: utility and limitations in seroprevalence and immunity studies https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879156/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879156/ [3] Risk of rapid evolutionary escape from biomedical interventions targeting SARS-CoV-2 spike protein https://pubmed.ncbi.nlm.nih.gov/33909660/ https://pubmed.ncbi.nlm.nih.gov/33909660/ [4] Antibodies elicited by mRNA-1273 vaccination bind more broadly to the receptor binding domain than do those from SARS-CoV-2 infection https://pubmed.ncbi.nlm.nih.gov/34103407/ https://pubmed.ncbi.nlm.nih.gov/34103407/
randcraw 5y ago
Inoculation with an mRNA vaccine provides recognition of few antigena (e.g. RBD). The size of the vaccine dosage and the delay of a month between doses is designed to create a strong recognition of the chosen antigens. Infection's response to key antigens like RBD is inherently more limited because: 1) immunity creates antibodies and T cells that target a wider range of antigens, and 2) exposure to COVID antigens usually fades after 7-10 days, limiting the immune system's time to build further defenses.
jyounker 5y ago
> Anyone with more experience in immunology care to weigh in on why the second paragraph there follows from the first? Naively, one might expect targeting a wider variety of places on on the COVID spike protein to result in better immunity against variants, not worse. Why is the article saying the opposite? The RBD is the part of the spike protein that latches onto the cell. Specifically it latches onto the ACE2 receptor. If the RBD changes too much then the virus can no longer infect its target cells (because it can't attach to ACE2 receptors). This means that there are probably strong limits on how much this section of the virus can change. Because we expect the RBD to change less than other areas, and because the mRNA vaccines recognize more of these possible changes, then we have a reasonable expectation that mRNA based immunity should continue to be effective. To make a crude analogy, ACE2 is a phillips head screw. The spike protein is a phillips screw driver. The tip of the screw driver is the RDB. Infection elicited antibodies recognize random spots all over the screw driver. mRNA vaccine elicited antibodies recognized spots all over the tip. Eventually you can turn the handle into a shape that won't be recognized, but there are strict limits on how much you can change the tip while still having it function as a philips screw driver. And of the ways that you can change the tip, the mRNA antibodies will match more of them than the naturally acquired ones. At least that's the expectation. There are still possible ways that the virus might evade; perhaps by making shields for the tip that block portions of the antibody, but this seems like it might be harder than changing the handle's shape.

rolph 5y ago

when you target many epitopes, you are shooting at the 10 inch ring; target one epitope of critical function [put one in center of mass] you are shooting the 2 inch ring. immune systems dont look at everything at once, they find something that sticks and and over trials sharpen the response until highest efficacy of antibody epitope combination is found. the vaccine is like a laser guided munition, natural immunity is like carpet cluster bombing; both highly effective but in different modalities.

bena 5y ago

The way I read it is that vaccine immunity is engineered towards COVID in general. It'll catch variants because they're still COVID. Natural immunity knows only of COVID-19 Alpha. But it knows it well. All those nooks and crannies the other variants may not have, the natural antibodies can latch on to.

rcxdude 5y ago

I think it's because the other parts of the virus are more likely to change over time, because there's lots of neutral mutations available: changes which don't affect fitness but do affect antibody response. The RBD by contrast is much more constrained: most mutations there result in a virus which can no longer infect cells, so it's much less likely to change (though of course any mutations which increase its effectiveness will be heavily selected for). This I think was one of the main reasons the spike protein was targeted by the mRNA viruses.

criticaltinker 5y ago

> Why is the article saying the opposite? The cited study in OP may have a slightly pro-vaccine bias, potentially because two authors have "the potential to receive a share of IP revenue" on a relevant patent, and because one author consults for Moderna. Regardless, the study presents scientifically accurate findings, but in a few places it tries to stretch those into questionable conclusions. For example, the authors write: > At first glance, the RBD targeting of the vaccine sera neutralization might seem likely to increase susceptibility to viral mutations, but the rest of our results suggest that this MAY not be the case. [4] So keep that tilt in mind when reading it. > one might expect targeting a wider variety of places on on the COVID spike protein to result in better immunity against variants Yes this is good intuition, here are excerpts from other literature illustrating why targeting a wide variety of SARS-COV-2 proteins can provide better immunity. In fact, this reasoning is why ongoing vaccine research is investigating formulations beyond the current solely spike protein focused vaccines. Notably, one shortcoming of the current mRNA vaccine formulations is that they do not induce nucleocapsid (N) protein antibodies - whereas natural infection does. > The nucleocapsid protein of SARS-CoV-2 has been suggested to be an important target for T cell responses. [1] > Firstly, this protein contains conserved cross-reactive T cell epitopes that are present among different coronaviruses, suggesting that it could be an ideal target for universal coronavirus vaccines. [1] > Secondly, the nucleocapsid protein is among the most abundant structural proteins in the coronavirus lifecycle, which may facilitate early antigen presentation and recognition by T cells. [1] > Previous knowledge on other related coronaviruses and the prompt sequencing of the SARS-CoV-2 genome early in the pandemic allowed to identify the spike (S) and the nucleocapsid (N) structural proteins as major targets of antibodies. [2] > The surface glycoprotein S, which contains the receptor-binding domain (RBD), has a better known function in immunity and is the leading antigen candidate for vaccine development. N is smaller than S, lacks a glycosylation site, and is extensively used in leading serodiagnostics kits due to its abundant expression during infection and early antibody response but its immunological relevance is less established. [2] > N forms ribonucleoprotein complexes during the virion assembly process by binding to the viral RNA genome and packing it into long helical structures. Its main function is to regulate viral RNA transcription during replication, promoting the synthesis of its own proteins while interfering with the metabolism, protein translation, and proliferation of the infected host cell. During the process of infection, N dissociates itself from the genome and is exposed to the host immune system, and its high immunogenicity has also prompted its exploration as vaccine target. [2] > Interestingly, significant protein similarity between SARS-CoV-1, SARS-CoV-2, and other HCoV has been reported for N, including a highly conserved motif in the N-terminal (NT) half of the protein (FYYLGTGP) and relevant immunodominant epitope regions. [2] > Evidence from multiple experimental studies showing that single RBD point mutations can lead to resistance to neutralizing convalescent plasma from multiple donors suggests that specific single mutants may be able to evade spike-targeting vaccinal immunity in many individuals and rapidly lead to spread of vaccine-resistant SARS-CoV-2. [3] [1] Combining spike- and nucleocapsid-based vaccines improves distal control of SARS-CoV-2 https://www.cell.com/cell-reports/pdf/S2211-1247(21)01108-6.pdf https://www.cell.com/cell-reports/pdf/S2211-1247(21)01108-6.... [2] Immunogenicity and crossreactivity of antibodies to the nucleocapsid protein of SARS-CoV-2: utility and limitations in seroprevalence and immunity studies https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879156/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879156/ [3] Risk of rapid evolutionary escape from biomedical interventions targeting SARS-CoV-2 spike protein https://pubmed.ncbi.nlm.nih.gov/33909660/ https://pubmed.ncbi.nlm.nih.gov/33909660/ [4] Antibodies elicited by mRNA-1273 vaccination bind more broadly to the receptor binding domain than do those from SARS-CoV-2 infection https://pubmed.ncbi.nlm.nih.gov/34103407/ https://pubmed.ncbi.nlm.nih.gov/34103407/

randcraw 5y ago

Inoculation with an mRNA vaccine provides recognition of few antigena (e.g. RBD). The size of the vaccine dosage and the delay of a month between doses is designed to create a strong recognition of the chosen antigens. Infection's response to key antigens like RBD is inherently more limited because: 1) immunity creates antibodies and T cells that target a wider range of antigens, and 2) exposure to COVID antigens usually fades after 7-10 days, limiting the immune system's time to build further defenses.

jyounker 5y ago

> Anyone with more experience in immunology care to weigh in on why the second paragraph there follows from the first? Naively, one might expect targeting a wider variety of places on on the COVID spike protein to result in better immunity against variants, not worse. Why is the article saying the opposite? The RBD is the part of the spike protein that latches onto the cell. Specifically it latches onto the ACE2 receptor. If the RBD changes too much then the virus can no longer infect its target cells (because it can't attach to ACE2 receptors). This means that there are probably strong limits on how much this section of the virus can change. Because we expect the RBD to change less than other areas, and because the mRNA vaccines recognize more of these possible changes, then we have a reasonable expectation that mRNA based immunity should continue to be effective. To make a crude analogy, ACE2 is a phillips head screw. The spike protein is a phillips screw driver. The tip of the screw driver is the RDB. Infection elicited antibodies recognize random spots all over the screw driver. mRNA vaccine elicited antibodies recognized spots all over the tip. Eventually you can turn the handle into a shape that won't be recognized, but there are strict limits on how much you can change the tip while still having it function as a philips screw driver. And of the ways that you can change the tip, the mRNA antibodies will match more of them than the naturally acquired ones. At least that's the expectation. There are still possible ways that the virus might evade; perhaps by making shields for the tip that block portions of the antibody, but this seems like it might be harder than changing the handle's shape.