Pre-existing immunity modulates responses to mRNA boosters

mRNA vaccines have shown high efficacy in preventing severe COVID-19, but breakthrough infections, emerging variants and waning antibody levels have warranted the use of boosters. Although mRNA boosters have been widely implemented, the extent to which pre-existing immunity influences the efficacy of boosters remains unclear. In a cohort of individuals primed with the mRNA-1273 or BNT162b2 vaccines, we observed that lower antibody levels before boost were associated with higher fold-increase in antibody levels after boost, suggesting that pre-existing antibody modulates the boosting capacity of mRNA vaccines. Mechanistic studies in mice show that pre-existing antibodies significantly limit antigen expression and priming of B cell responses after mRNA vaccination. Furthermore, we demonstrate that the relative superiority of an updated Omicron vaccine over the original vaccine is critically dependent on the serostatus of the host. These data demonstrate that pre-existing immunity dictates responses to mRNA vaccination, elucidating specific circumstances when updated SARS-CoV-2 vaccines confer superior protection to original vaccines.

Nucleocapsid-specific humoral responses improve the control of SARS-CoV-2

The spike protein of SARS-CoV-2 is a critical antigen present in all approved SARS-CoV-2 vaccines. This surface viral protein is also the target for all monoclonal antibody therapies, but it is unclear whether antibodies targeting other viral proteins can also improve protection against COVID-19. Here, we interrogate whether nucleocapsid-specific antibodies can improve protection against SARS-CoV-2. We first immunized mice with a nucleocapsid-based vaccine, and then transferred sera from these mice into naive mice. On the next day, the recipient mice were challenged intranasally with SARS-CoV-2 to evaluate whether nucleocapsid-specific humoral responses affect viral control. Interestingly, mice that received nucleocapsid-specific sera exhibited enhanced control of a SARS-CoV-2 infection. These findings provide the first demonstration that humoral responses specific to an internal coronavirus protein can help clear infection, warranting the inclusion of other viral antigens in next-generation SARS-CoV-2 vaccines and providing a rationale for the clinical evaluation of nucleocapsid-specific monoclonals to treat COVID-19. HighlightsA SARS-CoV-2 nucleocapsid vaccine elicits robust nucleocapsid-specific antibody responses. This nucleocapsid vaccine generates memory B cells (MBC). Nucleocapsid-specific humoral responses do not prevent SARS-CoV-2 infection. Nucleocapsid-specific humoral responses help control a SARS-CoV-2 infection.

Trail Making Test Normative Data for the German Older Population.

OBJECTIVE: We provide normative data for the Trail Making Test (TMT)-A and B and the derived scores B - A and B/A, for the German general population aged 57-84 years. METHODS: Data were derived from the third examination of the population-based Heinz Nixdorf Recall study. We excluded participants with a history of dementia or stroke, a depression score above cutoff (CES-D Center for Epidemiologic Studies Depression Scale score ≥ 18), or mild cognitive impairment according to a neurocognitive test battery. The normative sample (n = 2,182) was stratified by age, using the interval superposition approach, and by three levels of educational attainment (up to 10 years of schooling; >10 years of schooling; and university degree). RESULTS: We tabulated test performance scores at percentage rank thresholds 5, 10, 15, 20, 25, 50, 75, and 90. In multiple linear regression, TMT-A performance declined by 1 s each year of life, and TMT-B performance by 3 s; educational level had an impact of up to 30 s in TMT-B. TMT-B/A was only weakly associated with age and education. TMT-B and B - A correlated r = 0.96. Completion of the TMT-B within the time limit of 300 s was not achieved by 10.9% of participants >74 years, and especially by those >74 years who were on the lowest educational level (13.9%). CONCLUSIONS: For TMT-A, TMT-B, and B - A, the narrow age categorization and distinction between three educational levels proved meaningful. The 300 s limit for the TMT-B impedes the identification of thresholds for very low performance in this age group and needs reconsideration.

SARS coronavirus vaccines protect against different coronaviruses

Although SARS-CoV-2 vaccines have shown efficacy against SARS-CoV-2, it is unclear if they can also protect against other coronaviruses that may infect humans in the future. Here, we show that SARS-CoV-2 vaccination in humans elicits cross-reactive antibodies against other coronaviruses. Our studies in mice demonstrate that SARS-CoV-2 vaccination protects against a common cold coronavirus, and that SARS-CoV-1 vaccination protects against SARS-CoV-2. Similarly, infection with a common cold coronavirus also conferred enhanced protection from subsequent infections with other coronaviruses. Mechanistically, both T cells and antibodies mediated cross-protection. This is the first direct demonstration that coronavirus-specific immunity can confer heterologous protection in vivo, providing a rationale for universal coronavirus vaccines. HighlightsO_LISARS-CoV-2 vaccination elicits cross-reactive antibody against other coronaviruses in humans. C_LIO_LICOVID-19 patients generate cross-reactive antibody against other coronaviruses. C_LIO_LIA SARS-CoV-1 vaccine protects against SARS-CoV-2. C_LIO_LIPrior coronavirus infections improve immune protection following heterologous coronavirus challenges. C_LI

Limiting the priming dose of a SARS CoV-2 vaccine improves virus-specific immunity

Since late 2019, SARS-CoV-2 has caused a global pandemic that has infected 128 million people worldwide. Although several vaccine candidates have received emergency use authorization (EUA), there are still a limited number of vaccine doses available. To increase the number of vaccinated individuals, there are ongoing discussions about administering partial vaccine doses, but there is still a paucity of data on how vaccine fractionation affects vaccine-elicited immunity. We performed studies in mice to understand how the priming dose of a SARS CoV-2 vaccine affects long-term immunity to SARS CoV-2. We first primed C57BL/6 mice with an adenovirus-based vaccine encoding SARS CoV-2 spike protein (Ad5-SARS-2 spike), similar to that used in the CanSino and Sputnik V vaccines. This prime was administered either at a low dose (LD) of 106 PFU or at a standard dose (SD) of 109 PFU, followed by a SD boost in all mice four weeks later. As expected, the LD prime induced lower immune responses relative to the SD prime. However, the LD prime elicited immune responses that were qualitatively superior, and upon boosting, mice that were initially primed with a LD exhibited significantly more potent immune responses. Overall, these data demonstrate that limiting the priming dose of a SARS CoV-2 vaccine may confer unexpected benefits. These findings may be useful for improving vaccine availability and for rational vaccine design.