A small study, previously posted to the medRiv preprint server in early March, was recently published in the journal Science Immunology. The now peer-reviewed research led by E. John Wherry of the University of Pennsylvania Perelman School of Medicine finds people previously exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) produced a more robust immune response after receiving the first — but not the second mRNA vaccine.
The study results could influence future vaccination strategies as supplies continue to be limited in many countries and coronavirus variants continue to spread.
“SARS-CoV-2 naive individuals required two doses of vaccine to achieve optimal priming of antibodies, including neutralizing antibodies to the B.1.351 strain and memory B cells. In contrast, SARS-CoV-2 recovered subjects may only require a single vaccine dose to achieve peak antibody and memory B cell responses,” wrote the researchers.
How they did it
The ongoing study began recruiting participants from the University of Pennsylvania Health System in December 2020, with 44 individuals enrolled at the time of publication. All subjects were healthy during study enrollment with no history of chronic health conditions.
About 33 participants reported no previous SARS-CoV-2 infection, and 11 reported prior exposure ranging from 65 to 275 days before vaccination. The researchers found one individual who reported no prior SARS-CoV-2 exposure did have antibodies and memory B cells before vaccination and had to be reclassified as ‘recovered.’ Control groups were blood samples from non-vaccinated but recovered COVID-19 donors.
Everyone received a Pfizer-BioNTech or Moderna mRNA vaccine. To investigate changes in humoral immunity, the researchers collected blood samples at the start of the trial, 2 weeks after the first shot, the day of the second shot, and 1 week after the second mRNA dose.
.jpg "Antibody responses following mRNA vaccination in SARS-CoV-2 naïve and recovered individuals. A) UPenn Immune Health COVID vaccine study design. B) Concentration of anti-spike and anti-RBD IgG antibodies in vaccinated individuals over time. C) Focus reduction neutralization titer 50% (FRNT50) of vaccine-induced sera against pseudotyped virus expressing SARS-CoV-2 D614G (wild-type) or B.1.351 (South African) variant spike protein. D) Paired analysis of neutralization titers against D614G and B.1.351 in vaccine-induced sera at baseline (timepoint 1), pre-boost (timepoint 2), and post-boost (timepoint 4). E) Bivariate analysis of total anti-spike and anti-RBD binding antibodies with pseudovirus neutralization titers against D614G and B.1.351. Associations between total antibody levels and neutralizing ability were calculated using Spearman rank correlation and are shown with linear trend lines. Dotted lines indicate the limit of detection (LOD) for the assay. Statistics were calculated using unpaired Wilcoxon test (comparisons between timepoints and comparisons between naïve and recovered) or paired Wilcoxon test (comparisons between D614G and B.1.351) with Holm correction for multiple comparisons. Blue and red values indicate statistical comparisons within naïve or recovered groups. Black values indicate statistical comparisons between naïve or recovered groups.")
Antibody responses following mRNA vaccination in SARS-CoV-2 naïve and recovered individuals. A) UPenn Immune Health COVID vaccine study design. B) Concentration of anti-spike and anti-RBD IgG antibodies in vaccinated individuals over time. C) Focus reduction neutralization titer 50% (FRNT50) of vaccine-induced sera against pseudotyped virus expressing SARS-CoV-2 D614G (wild-type) or B.1.351 (South African) variant spike protein. D) Paired analysis of neutralization titers against D614G and B.1.351 in vaccine-induced sera at baseline (timepoint 1), pre-boost (timepoint 2), and post-boost (timepoint 4). E) Bivariate analysis of total anti-spike and anti-RBD binding antibodies with pseudovirus neutralization titers against D614G and B.1.351. Associations between total antibody levels and neutralizing ability were calculated using Spearman rank correlation and are shown with linear trend lines. Dotted lines indicate the limit of detection (LOD) for the assay. Statistics were calculated using unpaired Wilcoxon test (comparisons between timepoints and comparisons between naïve and recovered) or paired Wilcoxon test (comparisons between D614G and B.1.351) with Holm correction for multiple comparisons. Blue and red values indicate statistical comparisons within naïve or recovered groups. Black values indicate statistical comparisons between naïve or recovered groups.
Antibody responses before and after the first mRNA shot
Researchers initially found no IgG antibodies specific to SARS-CoV-2 in people with no prior viral exposure. In contrast, people who had recovered from previous coronavirus infection did show detectable antibody levels specific to either the spike protein or the spike receptor-binding domain before vaccination.
After the first mRNA dose, both groups produced antibodies, and recovered individuals showed a more tremendous boost in their SARS-CoV-2 immunity.
A noticeable difference between groups was observed after the second mRNA dose. Individuals with no prior exposure showed a more significant increase in their immune response after the second dose, but this was not observed in recovered individuals. Specifically, IgG antibodies specific to the receptor-binding domain were similar between groups 1 week after the second dose.
Differences in variant protection following immunization
The first shot showed a 50% protection against the D614G in people with no prior exposure. However, the first dose provided almost protection against the B.1.351 variant — notorious for mutations that allow it to evade immune responses — in both groups. Only 4 of 25 individuals had detectable neutralizing titers for it.
The neutralizing titers against the variants significantly increased after the second dose. Researchers measured significant increases in neutralizing titers for D614G, and 26 of 27 individuals showed neutralizing titers for B.1.351 a week after immunization.
For recovered individuals, the first dose produced more neutralizing antibodies. However, the second dose did not add increased protection in the form of neutralization titers against D614G or the B.1.351 variant.
Memory B cell levels following vaccination
Unlike people with no prior SARS-CoV-2 exposure, recovered individuals showed significant amounts of memory B cells specific to SARS-CoV-2, ranging from approximately 0.15 to 0.8% of total memory B cells.
But after the first shot, naïve individuals showed a significant rise in memory B cells targeting the spike protein or receptor-binding domain. Memory B cell levels further boosted after the second dose with levels comparable to non-vaccinated recovered individuals.
People recovering from prior infection boosted memory B cells after the first shot. However, there was no change after receiving the second dose.
Age may influence vaccine-induced immune response
After the first dose, researchers observed a negative trend between age and IgG levels targeting the receptor-binding domain in people naïve to SARS-CoV-2 infection. A clearer negative correlation was seen between age and memory B cell after the second dose.
The researchers note that none of the participants were over the age of 50. However, the results suggest age could be a potential influencer for immunization response.
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