Third COVID-19 Vaccine Dose Boosts Neutralizing Antibodies in Poor Responders (preprint)

Background: While evaluating COVID-19 vaccine responses using a rapid neutralizing antibody (NAb) test, we observed that 25% of RNA vaccine recipients did not neutralize >50%. We termed this group “vaccine poor responders” (VPRs). The objective of this study was to determine if individuals who neutralized <50% would remain VPRs, or if a third dose would elicit high levels of NAbs. Methods: 269 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 were evaluated. NAb 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. Results: Analysis of vaccine recipients revealed that 25% did not neutralize above 50% (Median neutralization = 21%, titers <1:80) within a month after their second dose. Twenty-three of these VPRs 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, VPRs showed an average 20-fold increase in NAb levels (range: 46%-99%). Conclusions: The results suggest that VPRs are not permanently poor responders; they can generate high NAb levels with an additional vaccine dose. Although it is not known what levels of NAbs protect from infection or disease, those in high-risk professions may wish to keep peripheral NAb levels high, limiting infection, and potential transmission.

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 (preprint)

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-N501Y MA30 , 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-N501Y MA30 . 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-N501Y MA30 .

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

Objective: To determine if poor responders to COVID19 RNA vaccines (<50% neutralisation) after two doses would remain poor responders, or if a third dose could elicit high levels of NAbs. Design: Clinical follow up study Setting: Academic and medical institutions in USA Participants: 269 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 Measures NAb levels were measured: i) 2 to4 weeks after a second vaccine dose, ii) 2 to 4 months after the second dose, iii) within 1 to 2 weeks prior to a third dose and iv) 2 to 4 weeks after a third RNA vaccine dose. Results: In 269 study participants, percent neutralisation ranged from 0% to 99% 2 to 4 weeks after a second vaccine dose. The majority of vaccine recipients (154/269, 57%) demonstrated NAb levels at greater than 75% 2 to 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 mRNA1273 vaccine 1 to 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% to 99%). Conclusions The 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.