SARS-CoV-2 Omicron Variant Infection of Individuals with High Titer Neutralizing Antibodies Post-3rd mRNA Vaccine Dose

BackgroundVaccination with COVID-19 mRNA vaccines prevent hospitalization and severe disease caused by wildtype SARS-CoV-2 and several variants, and likely prevented infection when serum neutralizing antibody (NAb) titers were >1:160. Preventing infection limits viral replication resulting in mutation, which can lead to the emergence of additional variants. MethodsDuring a longitudinal study to evaluate durability of a three-dose mRNA vaccine regimen (2 primary doses and a booster) using a rapid test that semi-quantitatively measures NAbs, the Omicron variant emerged and quickly spread globally. We evaluated NAb levels measured prior to symptomatic breakthrough infection, in groups infected prior to and after the emergence of Omicron. ResultsDuring the SARS-CoV-2 Delta variant wave, 93% of breakthrough infections in our study occurred when serum NAb titers were <1:80. In contrast, after the emergence of Omicron, study participants with high NAb titers that had received booster vaccine doses became symptomatically infected. NAb titers prior to infection were [≥]1:640 in 64% of the Omicron-infected population, [≥]1:320 (14%), and [≥]1:160 (21%). DiscussionThese results indicate that high titers of NAbs elicited by currently available mRNA vaccines do not protect against infection with the Omicron variant, and that mild to moderate symptomatic infections did occur in a vaccinated and boosted population, although did not require hospitalization.

Intranasal immunization with a vaccinia virus vaccine vector expressing pre-fusion stabilized SARS-CoV-2 spike fully protected mice against lethal challenge with the heavily mutated mouse-adapted SARS2-N501YMA30 strain of SARS-CoV-2

The Omicron SARS-CoV-2 variant has been designated a variant of concern because its spike protein is heavily mutated. In particular, Omicron spike is mutated at 5 positions (K417, N440, E484, Q493 and N501) that have been associated with escape from neutralizing antibodies induced by either infection with or immunization against the early Washington strain of SARS-CoV-2. The mouse-adapted strain of SARS-CoV-2, SARS2-N501YMA30, contains a spike that is also heavily mutated, with mutations at 4 of the 5 positions in Omicron spike associated with neutralizing antibody escape (K417, E484, Q493 and N501). In this manuscript we show that intranasal immunization with a pre-fusion stabilized Washington strain spike, expressed from a highly attenuated, replication-competent vaccinia virus construct, NYVAC-KC, fully protected mice against disease and death from SARS2-N501YMA30. Similarly, immunization by scarification on the skin fully protected against death, but not from mild disease. This data demonstrates that Washington strain spike, when expressed from a highly attenuated, replication-competent poxvirus, administered without parenteral injection can fully protect against the heavily mutated mouse-adapted SARS2-N501YMA30.

Third COVID-19 Vaccine Dose Boosts Neutralising Antibodies in Poor Responders

ObjectiveTo determine if poor responders to COVID-19 RNA vaccines (<50% neutralisation) after two doses would remain poor responders, or if a third dose could elicit high levels of NAbs. DesignClinical follow-up study SettingAcademic and medical institutions in USA Participants269 healthy individuals ranging in age from 19 to 80 (Average age = 51; 165 females and 104 males) who received either BNT162b2 (Pfizer) or mRNA1273 (Moderna) vaccines. Main Outcome MeasuresNAb levels were measured: i) 2-4 weeks after a second vaccine dose, ii) 2-4 months after the second dose, iii) within 1-2 weeks prior to a third dose and iv) 2-4 weeks after a third RNA vaccine dose. ResultsIn 269 study participants, percent neutralisation ranged from 0% to 99% 2-4 weeks after a second vaccine dose. The majority of vaccine recipients (154/269, 57%) demonstrated NAb levels at [≥]75% 2-4 weeks after their second dose. Our study also revealed that 25% of vaccine recipients did not neutralise above 50% (Median neutralisation = 21%, titers <1:80) within a month after their second dose. We called these individuals "vaccine poor responders" (VPRs). Twenty-three VPRs ranging in age from 31 to 79 (10 males, 13 females, average age = 62.5) independently obtained a third dose of either BNT162b2 or mRNA-1273 vaccine 1-8 months (average = 5 months) after their second dose. Within a month after their third dose, poor responders showed an average 20-fold increase in NAb levels (range 46%-99%). ConclusionsThe results suggest that poor responders are not permanently poor responders; they can generate high NAb levels with an additional vaccine dose-independent of mRNA vaccine manufacturer. Previous reports indicate that NAb levels decline much more rapidly than clinical protection from hospitalisation and disease, but that does not account for vaccine recipients who never generated high levels of NAbs after two doses. It is possible that poor responders are a source of breakthrough infections. Although it is not known what levels of NAbs protect from infection or disease, many vaccine recipients in high-risk professions may wish to keep peripheral NAb levels high, limiting infection, asymptomatic viral replication, and potential transmission.

Development of a Rapid Point-Of-Care Test that Measures Neutralizing Antibodies to SARS-CoV-2

BackgroundAfter receiving a COVID-19 vaccine, most recipients want to know if they are protected from infection and for how long. Since neutralizing antibodies are a correlate of protection, we developed a lateral flow assay (LFA) that measures levels of neutralizing antibodies from a drop of blood. The LFA is based on the principle that neutralizing antibodies block binding of the receptor-binding domain (RBD) to angiotensin-converting enzyme 2 (ACE2). MethodsThe ability of the LFA was assessed to correctly measure neutralization of sera, plasma or whole blood from patients with COVID-19 using SARS-CoV-2 microneutralization assays. We also determined if the LFA distinguished patients with seasonal respiratory viruses from patients with COVID-19. To demonstrate the usefulness of the LFA, we tested previously infected and non-infected COVID-19 vaccine recipients at baseline and after first and second vaccine doses. ResultsThe LFA compared favorably with SARS-CoV-2 microneutralization assays with an area under the ROC curve of 98%. Sera obtained from patients with seasonal coronaviruses did not show neutralizing activity in the LFA. After a single mRNA vaccine dose, 87% of previously infected individuals demonstrated high levels of neutralizing antibodies. However, if individuals were not previously infected only 24% demonstrated high levels of neutralizing antibodies after one vaccine dose. A second dose boosted neutralizing antibody levels just 8% higher in previously infected individuals, but over 63% higher in non-infected individuals. ConclusionsA rapid, semi-quantitative, highly portable and inexpensive neutralizing antibody test might be useful for monitoring rise and fall in vaccine-induced neutralizing antibodies to COVID-19.