Figure 1. Figure 1. Durability of neutralizing antibodies induced by mRNA enhancers according to prior SARS-CoV-2 infection.
Panel A shows neutralizing antibody titers against pseudotyped spike protein virus from ancestral severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with the D614G mutation and the B.1.1.529 (omicron) BA.1 subvariants; B.A. 2.12.1 and BA.4 and BA.5 (hereafter, BA.4/5) in serum samples obtained from healthcare workers without previous SARS-CoV-2 infection. Samples were obtained from participants who had received a booster dose of messenger RNA (mRNA) vaccine 1 to 3 months, 4 to 6 months, or 7 to 9 months earlier. Neutralizing antibody titers against virus with the D614G mutation and the minor BA.1, BA.2.12.1, and BA.4/5 subvariants in serum samples obtained from participants with prior SARS-CoV-2 infection are shown in Table B. Samples were taken according to the same time classes as in panel A. In both panels, dots represent individual samples and horizontal dashed lines represent the detection limit. Solid lines connect samples obtained from the same participant. Geometric mean values ​​for 50% neutralization titers (NT50) are shown at the top of the graphs for each time point. Panel C shows trend lines in the decay of neutralizing antibodies over the study period as determined by linear mixed-effects modeling with logistic repeated measures in participants without prior SARS-CoV-2 infection versus virus with the D614G mutation (slope, -0.0028 ; 95% CI, −0.0037 to −0.0018) or BA.1 subvariables (slope, −0.0031; 95% CI, −0.0048 to −0.0015), BA.2.12 .1 (slope, −0.5003 CI, −0.5003). to −0.0014), or BA.4/5 (slope, −0.0032; 95% CI, −0.0047 to −0.0016) and in participants with prior SARS-CoV-2 infection vs. with the D614G mutation (slope, −0.0027; 95% CI, −0.0050 to −0.0004) or BA.1 subvariants (slope, −0.0022; 95% CI, −0.0054 to −0.00 .0010), BA.2.12.1 (slope, −0.05−0.0015; −0.0016), or BA.4/5 (slope, −0.0019; 95% CI, −0.0047 to −0.0010 ). The 95% confidence intervals for each trendline slope have not been adjusted for multiplicity and should not be used in place of hypothesis testing. Booster resistance was significantly reduced in participants without primary infection than in those with primary infection, with neutralizing antibody titers, presented as 50% neutralizing titers (NT50), against all variants at 1 to 3 months post administration of the booster dose approximately 1.7 times (95% confidence interval [CI], 1.4 to 2.2) as high as those observed at 7 to 9 months after the booster dose (Figure 1 and Figure S1). Linear modeling showed a mean 30-day decay rate in neutralizing antibody titers of 17.53% (95% CI, 11.87 to 22.79) against virus with the D614G mutation, 19.50% (95% CI, 9.82 to 28.10 omic).1 subvariable, 18.44% (95% CI, 9.24 to 26.68) vs. BA.2.12.1 and 19.55% (95% CI, 10.54 to 27.66 ) versus BA.4/5 (Figure 1C). Participants with prior SARS-CoV-2 infection, including infection with the micron variant, had a somewhat less steep rate of decline in neutralizing antibody titers ( Figure 1B and 1C and Fig. S2 ), with 30-day rates of 17.07% ( 95% CI, 2.70 to 29.29) versus virus with the D614G mutation, 14.22% (95% CI, −6.87 to 31.13) versus the BA.1 subvariant, 9.97% ( 95% CI, −11.95 to .BA) 1 vs. 27.BA. .1 and 12.12% (95% CI, -7.14 to 27.94) versus BA.4/5 (Figure 1C). At all time points tested, all omicron subvariants, especially BA.4/5, had lower neutralizing antibody titers than virus with the D614G mutation. Two participants received a second booster dose of mRNA vaccine (Table S2). After a significant decrease in neutralizing antibody titers was observed approximately 4 months after receiving the initial booster dose in these participants, administration of a second booster dose resulted in recovery of neutralizing antibody titers (Fig. S3). The decline in booster persistence appeared to be slower than the decline previously reported for two doses of mRNA vaccine alone. had significant neutralization resistance. Our observed trends are consistent with waning vaccine protection and natural immunity,4,5 and our data suggest that both SARS-CoV-2 variant evolution and declining neutralizing antibody titers reduce enhancer-mediated immunity protection. Our anecdotal experience in two participants suggests that a fourth dose of vaccine may be effective. A variant-specific amplifier may become necessary as new variants are developed. Panke Qu, MSJulia N. Faraone, BSJohn P. Evans, MSYi-Min Zheng, MDLianbo Yu, Ph.D.Qin Ma, Ph.D.Claire CarlinGerard Lozanski, MDLinda J. Saif, Ph.D.Eugene M. Oltz, Ph.D.Richard J. Gumina, MD, Ph.D.Shan-Lu Liu, MD, Ph.D.Ohio State University, Columbus, Ohio [email protected] Supported by a fund provided by a private donor at Ohio University (to Dr. Liu), an award (U54CA260582, to Drs. Lozanski, Saif, Oltz, Gumina, and Liu) from the National Cancer Institute of the National Institutes of Health (NIH ), a Glenn Barber Fellowship (to Mr. Evans) from The Ohio State University College of Veterinary Medicine, fellowships (to Dr. Gumina) from the Robert J. Anthony Fund for Cardiovascular Research and the JB Cardiovascular Research Fund, and a grant ( R01 HD095881, to Dr. Saif) from the NIH. Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org. The content of this letter is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This letter was published on September 7, 2022, at NEJM.org. Mr. Qu, Ms. Faraone, and Mr. Evans contributed equally to this letter. 5 References