Single-shot Ad26 vaccine protects against SARS-CoV-2 in rhesus macaques.

A safe and effective vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may be required to end the coronavirus disease 2019 (COVID-19) pandemic1-8. For global deployment and pandemic control, a vaccine that requires only a single immunization would be optimal. Here we show the immunogenicity and protective efficacy of a single dose of adenovirus serotype 26 (Ad26) vector-based vaccines expressing the SARS-CoV-2 spike (S) protein in non-human primates. Fifty-two rhesus macaques (Macaca mulatta) were immunized with Ad26 vectors that encoded S variants or sham control, and then challenged with SARS-CoV-2 by the intranasal and intratracheal routes9,10. The optimal Ad26 vaccine induced robust neutralizing antibody responses and provided complete or near-complete protection in bronchoalveolar lavage and nasal swabs after SARS-CoV-2 challenge. Titres of vaccine-elicited neutralizing antibodies correlated with protective efficacy, suggesting an immune correlate of protection. These data demonstrate robust single-shot vaccine protection against SARS-CoV-2 in non-human primates. The optimal Ad26 vector-based vaccine for SARS-CoV-2, termed Ad26.COV2.S, is currently being evaluated in clinical trials.

Protective Efficacy of Rhesus Adenovirus COVID-19 Vaccines against Mouse-Adapted SARS-CoV-2.

The global COVID-19 pandemic has sparked intense interest in the rapid development of vaccines as well as animal models to evaluate vaccine candidates and to define immune correlates of protection. We recently reported a mouse-adapted SARS-CoV-2 virus strain (MA10) with the potential to infect wild-type laboratory mice, driving high levels of viral replication in respiratory tract tissues as well as severe clinical and respiratory symptoms, aspects of COVID-19 disease in humans that are important to capture in model systems. We evaluated the immunogenicity and protective efficacy of novel rhesus adenovirus serotype 52 (RhAd52) vaccines against MA10 challenge in mice. Baseline seroprevalence is lower for rhesus adenovirus vectors than for human or chimpanzee adenovirus vectors, making these vectors attractive candidates for vaccine development. We observed that RhAd52 vaccines elicited robust binding and neutralizing antibody titers, which inversely correlated with viral replication after challenge. These data support the development of RhAd52 vaccines and the use of the MA10 challenge virus to screen novel vaccine candidates and to study the immunologic mechanisms that underscore protection from SARS-CoV-2 challenge in wild-type mice. IMPORTANCE We have developed a series of SARS-CoV-2 vaccines using rhesus adenovirus serotype 52 (RhAd52) vectors, which exhibit a lower seroprevalence than human and chimpanzee vectors, supporting their development as novel vaccine vectors or as an alternative adenovirus (Ad) vector for boosting. We sought to test these vaccines using a recently reported mouse-adapted SARS-CoV-2 (MA10) virus to (i) evaluate the protective efficacy of RhAd52 vaccines and (ii) further characterize this mouse-adapted challenge model and probe immune correlates of protection. We demonstrate that RhAd52 vaccines elicit robust SARS-CoV-2-specific antibody responses and protect against clinical disease and viral replication in the lungs. Further, binding and neutralizing antibody titers correlated with protective efficacy. These data validate the MA10 mouse model as a useful tool to screen and study novel vaccine candidates, as well as the development of RhAd52 vaccines for COVID-19.

Protective efficacy of an attenuated Mtb ΔLprG vaccine in mice.

Bacille Calmette-Guerin (BCG), an attenuated whole cell vaccine based on Mycobacterium bovis, is the only licensed vaccine against Mycobacterium tuberculosis (Mtb), but its efficacy is suboptimal and it fails to protect against pulmonary tuberculosis. We previously reported that Mtb lacking the virulence genes lprG and rv1410c (ΔLprG) was highly attenuated in immune deficient mice. In this study, we show that attenuated ΔLprG Mtb protects C57BL/6J, Balb/cJ, and C3HeB/FeJ mice against Mtb challenge and is as attenuated as BCG in SCID mice. In C3HeB/FeJ mice, ΔLprG vaccination resulted in innate peripheral cytokine production and induced high polyclonal PPD-specific cytokine-secreting CD4+ T lymphocytes in peripheral blood. The ΔLprG vaccine afforded protective efficacy in the lungs of C3H/FeJ mice following both H37Rv and Erdman aerosolized Mtb challenges. Vaccine efficacy correlated with antigen-specific PD-1-negative CD4+ T lymphocytes as well as with serum IL-17 levels after vaccination. We hypothesize that induction of Th17 cells in lung is critical for vaccine protection, and we show a serum cytokine biomarker for IL-17 shortly after vaccination may predict protective efficacy.

Interaction between ischemic time and donor age under the new donor heart allocation system: Effect on post-transplant survival.

BACKGROUND: Ischemic time (IT) under the new heart transplant (HTx) allocation system has increased compared to the old system. We investigated the effect of IT and donor age on post-HTx survival. METHODS: The United Network for Organ Sharing (UNOS) database was analyzed to identify adult HTx between October 2015 and August 2020. Recipients were stratified by donor age, transplantation era, and IT. Kaplan-Meier and log-rank tests were used to compare 180-day post-HTx mortality. Cox proportional hazards modeling and propensity score matching were performed to adjust for confounders. RESULTS: Under the new system (N = 3654), IT≥4 h led to decreased survival compared to IT < 4 h (91.4% vs. 93.7%; P = .02), although this decrease was undetectable among those with donors ≥39 years old (90.4% vs. 91.1%; P = .73). IT≥4 h led to decreased survival with donors < 39 years old (91.7% vs. 94.6%; P < .01). Under the old system (N = 5987), IT≥4 h resulted in decreased survival (89.8% vs. 93.9%; P < .01), including with donors ≥39 years old (86.9% vs. 92.4%; P < .01). CONCLUSIONS: IT≥4 h remains a risk for post-HTx mortality under the new system. However, the magnitude of this effect is blunted when donor age is ≥39 years, likely secondary to increased allocation of these organs to lower status, more stable recipients.

Successful use of Impella 5.5 to manage cardiogenic shock complicated by COVID-19.

BACKGROUND: Acute decompensated heart failure in patients with coronavirus disease 2019 (COVID-19) is becoming increasingly common. AIMS: In this case report, we describe the successful use of an Impella 5.5 (Abiomed) to treat cardiogenic shock refractory to inotropic therapy. MATERIALS & METHODS: Transthoracic and transesophageal echocardiography confirmed severely diminished left ventricular ejection fraction and a reverse-transcription polymerase chain reaction test revealed that the patient was COVID-19 positive during his hospital admission. RESULTS: Following initiation of inotropic therapy, we placed an Impella 5.5 for further cardiac support. The patient's LVEF and cardiac index improved after 21 days on the Impella 5.5 and was maintained following explant. DISCUSSION & CONCLUSION: The findings reported here demonstrate successful use of an Impella 5.5 to improve native heart function in refractory cardiogenic shock and further indicate its use as an option for those in acute decompensated heart failure who have tested positive for COVID-19 infection.

COVID-19 vaccines: Immune correlates and clinical outcomes.

Severe disease due to COVID-19 has declined dramatically as a result of widespread vaccination and natural immunity in the population. With the emergence of SARS-CoV-2 variants that largely escape vaccine-elicited neutralizing antibody responses, the efficacy of the original vaccines has waned and has required vaccine updating and boosting. Nevertheless, hospitalizations and deaths due to COVID-19 have remained low. In this review, we summarize current knowledge of immune responses that contribute to population immunity and the mechanisms how vaccines attenuate COVID-19 disease severity.

Microaxial Left Ventricular Assist Device Versus Intraaortic Balloon Pump as a Bridge to Transplant.

BACKGROUND: Heart transplantation (HTx) candidates supported by Impella (Abiomed, Danvers, MA) or intraaortic balloon pump (IABP), who demonstrate evidence of cardiogenic shock, may qualify for waitlist status 2 without exception under the new donor heart allocation system. However limited data comparing Impella versus IABP as a bridge to HTx exist. METHODS: The United Network for Organ Sharing database was queried for adults listed and/or transplanted between January 2014 and February 2020. Temporal trends regarding Impella and IABP use were analyzed using the Royston trend test and χ2 test. Waitlist mortality was examined using Fine-Gray competing risks analysis. Post-HTx 180-day survival was analyzed using the Kaplan-Meier method and Cox proportional hazards models. RESULTS: Impella use increased from 0.2% in 2014 to 2.6% in 2020 (P < .01) and from 0.4% to 2.2% (P < .01) under the new allocation system. IABP use increased from 4.9% in 2014 to 27.6% in 2020 (P < .01) and from 6.7% to 26.6% (P < .01) under the new allocation system. Post-HTx survival was similar between groups (adjusted hazard ratio, 0.82; 95% CI, 0.38-1.78) despite more preoperative ventilation (3.6% vs 1.1%, P = .01) and higher model for end-stage liver disease excluding international normalized ratio scores (12.4 vs 9.5, P < .01) among Impella-supported recipients. Under the new system Impella-supported candidates were at higher risk of waitlist delisting compared with IABP-supported candidates (subhazard ratio, 2.42; 95% CI, 1.19-4.92). CONCLUSIONS: Post-HTx survival is comparable between Impella-supported and IABP-supported recipients despite worse preoperative profiles among Impella-supported recipients. Higher risk of waitlist delisting among Impella-supported candidates under the new allocation system requires close attention.

Durability and expansion of neutralizing antibody breadth following Ad26.COV2.S vaccination of mice.

Emerging SARS-CoV-2 variants with the potential to escape binding and neutralizing antibody responses pose a threat to vaccine efficacy. We recently reported expansion of broadly neutralizing activity of vaccine-elicited antibodies in humans 8 months following a single immunization with Ad26.COV2.S. Here, we assessed the 15-month durability of antibody responses and their neutralizing capacity to B.1.617.2 (delta) and B.1.351 (beta) variants following a single immunization of Ad26.COV2.S in mice. We report the persistence of binding and neutralizing antibody titers following immunization with a concomitant increase in neutralizing antibody breadth to delta and beta variants over time. Evaluation of bone marrow and spleen at 15 months postimmunization revealed that Ad26.COV2.S-immunized mice tissues contained spike-specific antibody-secreting cells. We conclude that immunization with Ad26.COV2.S elicits a robust immune response against SARS-CoV-2 spike, which expands over time to neutralize delta and beta variants more robustly, and seeds bone marrow and spleen with long-lived spike-specific antibody-secreting cells. These data extend previous findings in humans and support the use of a mouse model as a potential tool to further explore the dynamics of the humoral immune response following vaccination with Ad26.COV2.S.

Bridging With Extracorporeal Membrane Oxygenation Under the New Heart Allocation System: A United Network for Organ Sharing Database Analysis.

BACKGROUND: The effect of the new donor heart allocation system on survival following bridging to transplantation with venous-arterial extracorporeal membrane oxygenation remains unknown. The new allocation system places extracorporeal membrane oxygenation-supported candidates at the highest status. METHODS: The United Network for Organ Sharing database was queried for adults bridged to single-organ heart transplantation with extracorporeal membrane oxygenation from October 2006 to February 2020. Association between implementation of the new system and recipient survival was analyzed using Kaplan-Meier estimates, Cox proportional hazards models, and propensity score matching. RESULTS: Of 364 recipients included, 173 and 191 were transplanted under new and old systems, respectively. Compared with the old system, waitlist time was halved under the new system (5 versus 10 days, P<0.01); recipients also demonstrated lower rates of prior cardiac surgery (32.9% versus 44.5%, P=0.03) and preoperative ventilation (30.6% versus 42.4%, P=0.02). Unadjusted 180-day survival was 90.2% (95% CI, 84.7%-94.2%) and 69.6% (95% CI, 62.6%-76.1%) under the new and old systems, respectively. Cox proportional hazards analysis demonstrated listing and transplantation under the new system to be an independent predictor of post-transplant survival (adjusted hazard ratio, 0.34 [95% CI 0.20-0.59]). Propensity score matching demonstrated a similar trend (hazard ratio, 0.36 [95% CI, 0.19-0.66]). Candidates listed under the new system were significantly less likely to experience waitlist mortality or deterioration (subhazard ratio, 0.38 [95% CI, 0.25-0.58]) and more likely to survive to transplant (subhazard ratio, 4.29 [95% CI, 3.32-5.54]). CONCLUSIONS: Recipients transplanted following extracorporeal membrane oxygenation bridging to transplantation under the new system achieve greater 180-day survival compared with the old and demonstrate less preoperative comorbidity. Waitlist outcomes have also improved significantly under the new allocation system.

Protective efficacy of rhesus adenovirus COVID-19 vaccines against mouse-adapted SARS-CoV-2.

The global COVID-19 pandemic has sparked intense interest in the rapid development of vaccines as well as animal models to evaluate vaccine candidates and to define immune correlates of protection. We recently reported a mouse-adapted SARS-CoV-2 virus strain (MA10) with the potential to infect wild-type laboratory mice, driving high levels of viral replication in respiratory tract tissues as well as severe clinical and respiratory symptoms, aspects of COVID-19 disease in humans that are important to capture in model systems. We evaluated the immunogenicity and protective efficacy of novel rhesus adenovirus serotype 52 (RhAd52) vaccines against MA10 challenge in mice. Baseline seroprevalence is lower for rhesus adenovirus vectors than for human or chimpanzee adenovirus vectors, making these vectors attractive candidates for vaccine development. We observed that RhAd52 vaccines elicited robust binding and neutralizing antibody titers, which inversely correlated with viral replication after challenge. These data support the development of RhAd52 vaccines and the use of the MA10 challenge virus to screen novel vaccine candidates and to study the immunologic mechanisms that underscore protection from SARS-CoV-2 challenge in wild-type mice. IMPORTANCE: We have developed a series of SARS-CoV-2 vaccines using rhesus adenovirus serotype 52 (RhAd52) vectors, which exhibits a lower seroprevalence than human and chimpanzee vectors, supporting their development as novel vaccine vectors or as an alternative Ad vector for boosting. We sought to test these vaccines using a recently reported mouse-adapted SARS-CoV-2 (MA10) virus to i) evaluate the protective efficacy of RhAd52 vaccines and ii) further characterize this mouse-adapted challenge model and probe immune correlates of protection. We demonstrate RhAd52 vaccines elicit robust SARS-CoV-2-specific antibody responses and protect against clinical disease and viral replication in the lungs. Further, binding and neutralizing antibody titers correlated with protective efficacy. These data validate the MA10 mouse model as a useful tool to screen and study novel vaccine candidates, as well as the development of RhAd52 vaccines for COVID-19.

Immunity elicited by natural infection or Ad26.COV2.S vaccination protects hamsters against SARS-CoV-2 variants of concern.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern have emerged and may pose a threat to both the efficacy of vaccines based on the original WA1/2020 strain and the natural immunity induced by infection with earlier SARS-CoV-2 variants. We investigated how mutations in the spike protein of circulating SARS-CoV-2 variants, which have been shown to partially evade neutralizing antibodies, affect natural and vaccine-induced immunity. We adapted a Syrian hamster model of moderate to severe clinical disease for two variant strains of SARS-CoV-2: B.1.1.7 (alpha variant) and B.1.351 (beta variant). We then assessed the protective efficacy conferred by either natural immunity from WA1/2020 infection or by vaccination with a single dose of the adenovirus serotype 26 vaccine, Ad26.COV2.S. Primary infection with the WA1/2020 strain provided potent protection against weight loss and viral replication in lungs after rechallenge with WA1/2020, B.1.1.7, or B.1.351. Ad26.COV2.S induced cross-reactive binding and neutralizing antibodies that were reduced against the B.1.351 strain compared with WA1/2020 but nevertheless still provided robust protection against B.1.351 challenge, as measured by weight loss and pathology scoring in the lungs. Together, these data support hamsters as a preclinical model to study protection against emerging variants of SARS-CoV-2 conferred by prior infection or vaccination.

DNA vaccine protection against SARS-CoV-2 in rhesus macaques.

The global coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has made the development of a vaccine a top biomedical priority. In this study, we developed a series of DNA vaccine candidates expressing different forms of the SARS-CoV-2 spike (S) protein and evaluated them in 35 rhesus macaques. Vaccinated animals developed humoral and cellular immune responses, including neutralizing antibody titers at levels comparable to those found in convalescent humans and macaques infected with SARS-CoV-2. After vaccination, all animals were challenged with SARS-CoV-2, and the vaccine encoding the full-length S protein resulted in >3.1 and >3.7 log10 reductions in median viral loads in bronchoalveolar lavage and nasal mucosa, respectively, as compared with viral loads in sham controls. Vaccine-elicited neutralizing antibody titers correlated with protective efficacy, suggesting an immune correlate of protection. These data demonstrate vaccine protection against SARS-CoV-2 in nonhuman primates.

SARS-CoV-2 infection protects against rechallenge in rhesus macaques.

An understanding of protective immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for vaccine and public health strategies aimed at ending the global coronavirus disease 2019 (COVID-19) pandemic. A key unanswered question is whether infection with SARS-CoV-2 results in protective immunity against reexposure. We developed a rhesus macaque model of SARS-CoV-2 infection and observed that macaques had high viral loads in the upper and lower respiratory tract, humoral and cellular immune responses, and pathologic evidence of viral pneumonia. After the initial viral clearance, animals were rechallenged with SARS-CoV-2 and showed 5 log10 reductions in median viral loads in bronchoalveolar lavage and nasal mucosa compared with after the primary infection. Anamnestic immune responses after rechallenge suggested that protection was mediated by immunologic control. These data show that SARS-CoV-2 infection induced protective immunity against reexposure in nonhuman primates.

Ad26 vaccine protects against SARS-CoV-2 severe clinical disease in hamsters.

Coronavirus disease 2019 (COVID-19) in humans is often a clinically mild illness, but some individuals develop severe pneumonia, respiratory failure and death1-4. Studies of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in hamsters5-7 and nonhuman primates8-10 have generally reported mild clinical disease, and preclinical SARS-CoV-2 vaccine studies have demonstrated reduction of viral replication in the upper and lower respiratory tracts in nonhuman primates11-13. Here we show that high-dose intranasal SARS-CoV-2 infection in hamsters results in severe clinical disease, including high levels of virus replication in tissues, extensive pneumonia, weight loss and mortality in a subset of animals. A single immunization with an adenovirus serotype 26 vector-based vaccine expressing a stabilized SARS-CoV-2 spike protein elicited binding and neutralizing antibody responses and protected against SARS-CoV-2-induced weight loss, pneumonia and mortality. These data demonstrate vaccine protection against SARS-CoV-2 clinical disease. This model should prove useful for preclinical studies of SARS-CoV-2 vaccines, therapeutics and pathogenesis.