New paper suggests previously infected individuals get full benefit after 1st vaccine dose

A research team at University of Pennsylvania led by my immunologist colleague John Wherry just posted a paper on medRXiv looking at the response of mRNA vaccinated individuals' immune systems over time, looking both at levels of antibodies targeting the key spike protein as well as memory B cells that can regenerate necessary antibodies when later exposed to the virus, a key component of long-term immune response.

The key take-home result was that both doses were necessary to get the full immune response from those not previously infected, but those previously infected seemed to get the full immune boost from the first dose, and the second dose appeared unnecessary. This suggests the importance of both doses for those not previously infected, but that those previously infected should perhaps only be getting a single dose as a booster.

In this blog post, I'll summarize these key results and then list the other interesting findings they found in this research: Brief Summary of Paper

• This study looked at blood immune markers from 44 vaccinated individuals at the University of Pennsylvania Health System

• 33 were SARS-CoV-2 naive (i.e. not previously infected) and 11 were SARS-CoV-2 recovered (i.e. previously infected).

• They measured various targeted SARS-CoV-2 antibodies, including antibodies that target the receptor binding domain (RBD) of the spike protein, probably the most pivotal location in the virus for neutralizing antibodies.

• They also measured SARS-CoV-2 specific memory B cells, including ones targeting the spike protein and the RBD of the spike protein. These B cells can effectively code "memory" for how to regenerate the key antibodies if exposed to the virus in the future. These memory B-cells are key to long term immune response. Even when antibody levels wane, these memory B-cells can regenerate the antibodies as needed upon exposure, which is why antibody levels are not sufficient for measuring immune response.

• They measured these markers at 4 time points: baseline (pre 1st dose), 2 weeks after first dose, day of booster (2nd dose), and 1 week after booster.

Both doses important for SARS-CoV-2 naive, but first dose provides full benefit for SARS-CoV-2 recovered

Below is a plot from the paper of the antibody levels targeting the RBD of the spike protein at the 4 time points for SARS-CoV-2 naive (blue) and SARS-CoV-2 recovered (red), with the center line of the box plot indicating the median levels and the ends of the plots indicating the minimum and maximum values observed.

First, we see that at baseline, the SARS-CoV-2 naive had almost no antibodies, and the SARS-CoV-2 recovered had very low levels of antibodies. Two weeks after the first dose, the SARS-CoV-2 naive group showed substantial antibody response comparable to the SARS-CoV-2 recovered at baseline, and remained at similar levels up until the booster. A week after the booster, we see the antibody levels jumped to much higher levels, up to where the SARS-CoV-2 recovered vaccinated were. This shows the importance of SARS-CoV-2 naive individuals getting both doses in order to get the full antibody levels. Looking at the SARS-CoV-2 recovered group, we see a large jump in antibody levels after the first dose, but these levels don't further increase with the booster. It appears the antibody levels have reached a threshold and don't further increase after the first dose. Since antibodies don't tell the entire story, they also looked at memory B cells. Here is a plot of the memory B cells focusing on the RBD of the spike protein:

First, at baseline we see that the SARS-CoV-2 recovered had much higher levels of memory B-cells than the SARS-CoV-2 naive, demonstrating the existing immunity they retained from their previous infection. Their B-cell levels sharply increased after first vaccine dose, demonstrating that the vaccine provided a boost to their immune system. However, while the SARS-CoV-2 naive continued to increase in B-cells after the boost (2nd dose), the B-cell levels for the SARS-CoV-2 recovered group plateaued after the first dose, with no further increase after the 2nd dose. Together, these results suggest that individuals without previous infection clearly benefited from both doses as measured both by antibodies and memory B cell levels, but previously infected individuals saw a clear boost in antibody levels and memory B cell levels after the first dose, but no further increase from the second dose.

This is important, suggesting perhaps those previously infected should just get a single dose, and highlighting the importance of others getting both doses in order to obtain the full level of immune response.

The paper also had some other key results, including:

• Side-effect severity correlated with the short-term antibody response, but not the memory B-cell response, providing encouragement to those who don't have immediate side effects that the lack of side effects does not mean the vaccine is not conferring immune protection.

• For previously infected individuals, their post-vaccination antibody levels were strongly correlated with pre-vaccination B-cell levels, demonstrating the key role in B-cells in generating antibodies upon exposure.

• There was no association between age and antibody levels post-vaccination, but there was for B-cells. While all ages generated substantial memory B-cells, the levels were higher in younger individuals, showing there is likely an age-based effect in vaccine response.

• The antibody levels immediately post-vaccination were not correlated with the post-vaccination memory B cell response, showing that the short term antibody levels do not measure the full antibody response. This provides encouragement that waning antibody levels do not mean loss of immune protection, and also highlights the need to measure memory B-cells, not just antibodies, in measuring the effect of vaccination or durability of immune protection.

This is very exciting and impactful work, I am hopeful that this will be published in a high impact peer reviewed journal shortly.