Early post-infection treatment of SARS-CoV-2 infected macaques with human convalescent plasma with high neutralizing activity had no antiviral effects but moderately reduced lung inflammation.

Early in the SARS-CoV-2 pandemic, there was a high level of optimism based on observational studies and small controlled trials that treating hospitalized patients with convalescent plasma from COVID-19 survivors (CCP) would be an important immunotherapy. However, as more data from controlled trials became available, the results became disappointing, with at best moderate evidence of efficacy when CCP with high titers of neutralizing antibodies was used early in infection. To better understand the potential therapeutic efficacy of CCP, and to further validate SARS-CoV-2 infection of macaques as a reliable animal model for testing such strategies, we inoculated 12 adult rhesus macaques with SARS-CoV-2 by intratracheal and intranasal routes. One day later, 8 animals were infused with pooled human CCP with a high titer of neutralizing antibodies (RVPN NT50 value of 3,003), while 4 control animals received normal human plasma. Animals were monitored for 7 days. Animals treated with CCP had detectable but low levels of antiviral antibodies after infusion. In comparison to the control animals, CCP-treated animals had similar levels of viral RNA in upper and lower respiratory tract secretions, similar detection of viral RNA in lung tissues by in situ hybridization, but lower amounts of infectious virus in the lungs. CCP-treated animals had a moderate, but statistically significant reduction in interstitial pneumonia, as measured by comprehensive lung histology. Thus overall, therapeutic benefits of CCP were marginal and inferior to results obtained earlier with monoclonal antibodies in this animal model. By highlighting strengths and weaknesses, data of this study can help to further optimize nonhuman primate models to provide proof-of-concept of intervention strategies, and guide the future use of convalescent plasma against SARS-CoV-2 and potentially other newly emerging respiratory viruses.

Early treatment with a combination of two potent neutralizing antibodies improves clinical outcomes and reduces virus replication and lung inflammation in SARS-CoV-2 infected macaques.

There is an urgent need for effective therapeutic interventions against SARS-CoV-2, including new variants that continue to arise. Neutralizing monoclonal antibodies have shown promise in clinical studies. We investigated the therapeutic efficacy of a combination of two potent monoclonal antibodies, C135-LS and C144-LS that carry half-life extension mutations, in the rhesus macaque model of COVID-19. Twelve young adult macaques (three groups of four animals) were inoculated intranasally and intra-tracheally with a high dose of SARS-CoV-2 and 24 hours later, treated intravenously with a high (40 mg/kg) or low (12 mg/kg) dose of the C135-LS and C144-LS antibody combination, or a control monoclonal antibody. Animals were monitored for 7 days. Compared to the control animals, animals treated with either dose of the anti-SARS-CoV-2 antibodies showed similarly improved clinical scores, lower levels of virus replication in upper and lower respiratory tract, and significantly reduced interstitial pneumonia, as measured by comprehensive lung histology. In conclusion, this study provides proof-of-concept in support of further clinical development of these monoclonal antibodies against COVID-19 during early infection.

Clinical and videofluoroscopic outcomes of laparoscopic treatment for sliding hiatal hernia and associated gastroesophageal reflux in brachycephalic dogs.

OBJECTIVE: To describe a laparoscopic technique for treatment of sliding hiatal hernia (SHH) and associated gastroesophageal reflux (GER) in brachycephalic dogs and document clinical and videofluoroscopic outcomes postoperatively. STUDY DESIGN: Prospective clinical trial. ANIMALS: Eighteen client-owned dogs. METHODS: A three-port laparoscopic approach was used. Intracorporeal suturing was used for hiatal plication and esophagopexy, and left-sided laparoscopic or laparoscopic-assisted gastropexy was performed. A standardized canine dysphagia assessment tool (CDAT) questionnaire was completed by owners pre- and postoperatively. Videofluoroscopic swallow studies (VFSS) were used to evaluate esophageal function, and impedance planimetry was used to assess lower esophageal sphincter geometry preoperatively and in a subset of dogs postoperatively. RESULTS: Median age was 27.5 (range 5-84) months. Conversion to open surgery was necessary in 1 (5.5%) of 18 dogs. Regurgitation after eating, and associated with activity/exercise, improved significantly when comparing pre- and postoperative CDAT assessments. Hiatal hernia and GER severity scores improved significantly between pre- and postoperative VFSS assessments, whereas SHH and GER frequency scores did not. One dog developed pneumothorax intraoperatively, underwent cardiopulmonary arrest, and died. Minor complications included splenic (n = 6) and hepatic lacerations (n = 3) that did not require specific therapy. CONCLUSION: A laparoscopic approach to treatment of SHH and GER led to improvements in clinical and VFSS indices in the majority of brachycephalic dogs. However, a subset of dogs still demonstrated some clinical signs postoperatively. CLINICAL RELEVANCE: In experienced hands, laparoscopic treatment of SHH and GER offers a minimally invasive alternative to open surgery.

Evaluation of radiographic predictors of left heart enlargement in dogs with known or suspected cardiovascular disease.

Radiographic assessment of heart size is important for clinical management of dogs with cardiovascular disease (CVDz). We sought to compare the ability of vertebral heart size (VHS), vertebral left atrial size (VLAS), and radiologists' assessment of left atrial size (RadLAE) to predict echocardiographic left atrial size (EchoLAE), an important marker of left heart disease severity. We also compared the ability of VHS and VLAS to predict echocardiographic criteria for ACVIM stage B2 (EchoB2) in dogs with myxomatous mitral valve disease (MMVD). This prospective observational study enrolled 183 dogs with known or suspected CVDz that had an echocardiographic examination and thoracic radiographs obtained within 24 h. Compared to increased VHS, VLAS >2.3 was a more accurate predictor of EchoLAE (P = .002). VLAS >2.3 and RadLAE (both P <.0001) were independently associated with EchoLAE but VHS was not (P = .45). Optimal cutoffs for VLAS and VHS to predict EchoLAE were >2.3 vertebrae (sensitivity [Sn] = 90.3%, specificity [Sp] = 73.6%) and >11.1 vertebrae (Sn = 75.8%, Sp = 76.0%), respectively. Diagnostic accuracy of VLAS (AUC 0.84, 95% CI 0.73-0.92) and VHS (AUC 0.78, 95% CI 0.66-0.88) to predict EchoB2 in dogs with subclinical MMVD (n = 64) were not significantly different (P = .17). Results demonstrate that VLAS and RadLAE were superior indicators of EchoLAE compared to VHS in dogs with known or suspected CVDz. Both VLAS and VHS are useful predictors of EchoB2 in dogs with subclinical MMVD. When echocardiography is unavailable, VLAS represents a useful radiographic measurement to aid clinical management of dogs with known or suspected CVDz.

Ultrasonographic characterization of cervical lymph nodes in healthy dogs.

Ultrasonography provides a minimally invasive method to evaluate the cervical lymph nodes in dogs as part of staging head and neck cancer; however, standardized cohesive reports of the normal lymph node size and appearance are lacking. The purpose of this prospective, descriptive, reference interval study was to characterize the ultrasonographic appearance of cervical lymph nodes in 27 clinically healthy dogs. The size, shape, echogenicity, and margination of the mandibular, medial retropharyngeal, and superficial cervical lymph nodes were evaluated and correlated with age, breed, sex, body weight, and stage of dental disease. The appearance of the lymph nodes was variable among the population. The majority were cigar or ovoid in shape with smooth margins. The echogenicity of the mandibular lymph nodes was predominantly hypoechoic whereas the medial retropharyngeal lymph nodes were predominantly isoechoic compared to the salivary glands. The superficial cervical lymph nodes were predominantly hyperechoic to the surrounding muscle bellies. Higher body weight and younger age were associated with increased size in the medial retropharyngeal and superficial cervical lymph nodes (P-values < .05). Sex and breed were not found to correlate with lymph node characteristics, and there was no trend noted in lymph node appearance associated with dental disease. These data establish normal parameters for the ultrasonographic size and appearance of cervical lymph nodes in dogs and can provide a reference of comparison for future canine cervical ultrasounds, which can be considered for routine staging procedures for head and neck cancer.

The prevalence of dynamic pharyngeal collapse is high in brachycephalic dogs undergoing videofluoroscopy.

The aim of this retrospective study was to determine the frequency of pharyngeal collapse in a large group of brachycephalic dogs undergoing videofluoroscopic assessment of swallowing or airway diameter. We hypothesized that brachycephalic dogs would have pharyngeal collapse more frequently than dolichocephalic or mesocephalic dogs with or without airway collapse. The medical records database was searched for brachycephalic dogs undergoing videofluoroscopy of swallowing or airway diameter between January 1, 2006 and December 31, 2015. A cohort of dolichocephalic/mesocephalic dogs with videofluoroscopically confirmed airway collapse was age and time matched for comparison. A control group of dolichocephalic/mesocephalic dogs that did not have documented airway collapse was also evaluated. All fluoroscopic studies were assessed by a board certified veterinary radiologist for the presence and degree of pharyngeal collapse. Results demonstrate that pharyngeal collapse was significantly more common in brachycephalic dogs (58/82; 72%) than in nonbrachycephalic dogs with (7/25; 28%) and without (2/30; 7%) airway collapse. Pharyngeal collapse is more prevalent in brachycephalic dogs undergoing videofluoroscopy than in dolichocephalic/mesocephalic dogs with or without airway collapse.

Ultrasonography does not consistently detect parathyroid glands in healthy cats.

Ultrasound is used to evaluate the parathyroid glands of several species but there are limited reports of its use in cats. With this prospective anatomic study, we hypothesized that ultrasound could identify two parathyroid glands as hypoechoic nodules associated with each thyroid lobe and that a normal size range could be established. Six cat cadavers were imaged with ultrasound and histopathology of the thyroid and parathyroid tissue was performed for comparison. In addition, clinically healthy adult cats were prospectively recruited and placed in Group 1 (2-6 years; n = 11) or Group 2 (7-13 years; n = 9). Ultrasound of the cervical region was performed using a 7-15 MHz linear transducer. Number, size, and location of all hypoechoic nodules within or immediately adjacent to the thyroid lobes were documented. Ultrasound identified between 0-6 hypoechoic nodules per thyroid lobe in cat cadavers and between 0-3 hypoechoic nodules per thyroid lobe in clinically healthy cats, which does not correlate with the normal anatomy. In conclusion, parathyroid glands were frequently not ultrasonographically observed or were not distinguishable from thyroid tissue and this problem was worse in older cats because of the prevalence of nodular thyroid lesions, which primarily included foci of adenomatous hyperplasia.

Diagnostic outcome of contrast videofluoroscopic swallowing studies in 216 dysphagic dogs.

Determining the anatomic and functional origin for dysphagia is critical for development of an appropriate therapeutic plan and determination of the prognosis. The purpose of this retrospective study was to report the quantitative and qualitative outcome of contrast videofluoroscopic swallowing studies in a large cohort of dysphagic dogs presenting to a tertiary veterinary care hospital. The videofluoroscopic swallowing studies were reviewed to generate values for pharyngeal constriction ratio, timing of swallowing events (maximum pharyngeal contraction, opening of upper esophageal sphincter, closing of upper esophageal sphincter, and reopening of epiglottis), type of esophageal peristalsis generated, and esophageal transit time. One or more anatomic locations for origin of dysphagia were assigned (pharyngeal, cricopharyngeal, esophageal (primary motility disorder), other esophageal (stricture, vascular ring anomaly, mass), lower esophageal sphincter/hiatus. Sixty-one of 216 studies (28%) were deemed unremarkable. Twenty-seven of 216 dogs (13%) had pharyngeal dysphagia, 17/216 dogs (8%) had cricopharyngeal dysphagia, 98/216 dogs (45%) had dysphagia secondary to esophageal dysmotility, 19/216 dogs (9%) had dysphagia secondary to focal esophageal disorders, and 97/216 dogs (45%) had dysphagia of lower esophageal sphincter/hiatus origin. Multiple abnormalities were present in 82/216 (38%) dogs. Elevated pharyngeal constriction ratio was associated with pharyngeal, cricopharyngeal, and esophageal motility disorders, delayed upper esophageal sphincter opening was associated with cricopharyngeal disorders, a lower percentage of primary esophageal peristaltic waves was associated with cricopharyngeal, pharyngeal, or primary esophageal motility disorders. In conclusion, videofluoroscopic swallowing studies was pivotal in the diagnosis of dysphagia with 155/216 (72%) dogs receiving a final diagnosis.

INDIRECT COMPUTED TOMOGRAPHIC LYMPHOGRAPHY FOR ILIOSACRAL LYMPHATIC MAPPING IN A COHORT OF DOGS WITH ANAL SAC GLAND ADENOCARCINOMA: TECHNIQUE DESCRIPTION.

Sentinel lymph node mapping can help to direct surgical oncologic staging and metastatic disease detection in patients with complex lymphatic pathways. We hypothesized that indirect computed tomographic lymphography (ICTL) with a water-soluble iodinated contrast agent would successfully map lymphatic pathways of the iliosacral lymphatic center in dogs with anal sac gland carcinoma, providing a potential preoperative method for iliosacral sentinel lymph node identification in dogs. Thirteen adult dogs diagnosed with anal sac gland carcinoma were enrolled in this prospective, pilot study, and ICTL was performed via peritumoral contrast injection with serial caudal abdominal computed tomography scans for iliosacral sentinel lymph node identification. Technical and descriptive details for ICTL were recorded, including patient positioning, total contrast injection volume, timing of contrast visualization, and sentinel lymph nodes and lymphatic pathways identified. Indirect CT lymphography identified lymphatic pathways and sentinel lymph nodes in 12/13 cases (92%). Identified sentinel lymph nodes were ipsilateral to the anal sac gland carcinoma in 8/12 and contralateral to the anal sac gland carcinoma in 4/12 cases. Sacral, internal iliac, and medial iliac lymph nodes were identified as sentinel lymph nodes, and patterns were widely variable. Patient positioning and timing of imaging may impact successful sentinel lymph node identification. Positioning in supported sternal recumbency is recommended. Results indicate that ICTL may be a feasible technique for sentinel lymph node identification in dogs with anal sac gland carcinoma and offer preliminary data to drive further investigation of iliosacral lymphatic metastatic patterns using ICTL and sentinel lymph node biopsy.

Feasibility of quantitative contrast ultrasound imaging of bladder tumors in dogs.

The purpose of this pilot study was to assess the feasibility of Cadence contrast pulse sequencing ultrasound to predict clinical and angiogenic tumor response in dogs undergoing chemotherapy. Contrast ultrasound facilitated visualization of bladder tumors but failed to identify a straightforward relationship between ultrasound measures and clinical outcome.

Faisabilité de l'échographie de contraste quantitative des tumeurs des reins chez les chiens. Cette étude pilote avait pour but d'évaluer la faisabilité de l'échographie de contraste par séquençage des pulsations (CadenceTM) pour prédire la réponse clinique et angiogénique de la tumeur chez les chiens subissant la chimiothérapie. L'échographie de contraste a facilité la visualisation des tumeurs rénales mais n'a pas réussi à identifier un lien direct entre les mesures de l'échographie et le résultat clinique.(Traduit par Isabelle Vallières).

EFFECT OF BOLUS SIZE ON DEGLUTITION AND ESOPHAGEAL TRANSIT IN HEALTHY DOGS.

Contrast videofluoroscopy is the gold standard procedure for evaluating dysphagia in humans, but quantitative measures vary depending on bolus size and consistency. We hypothesized that quantitative measures made during videofluoroscopy of swallowing in dogs would differ between bolus sizes and consistencies. Ten healthy adult dogs were enrolled a prospective, crossover experimental study and underwent contrast videofluoroscopy while swallowing liquid (5, 10, and 15 ml) and canned food (3, 8, and 12 g) boluses. Maximum pharyngeal contraction occurred significantly later with medium solid boluses than with medium liquid boluses, with a mean difference of 0.021 s (adjusted P = 0.042). Upper esophageal sphincter opening occurred significantly earlier with large solid boluses than with medium solid boluses, with a mean difference of 0.018 s (adjusted P = 0.025). Thoracic esophageal transit time was significantly longer with small solid boluses than with small liquid boluses, with a mean difference of 0.68 s (adjusted P = 0.004). Odds of primary esophageal peristalsis occurring were significantly (18.5 times) higher with large solid vs. large liquid boluses (adjusted P = 0.031). No other statistical comparisons reached significance. Based on these results, we recommend a standardized approach to videofluoscopy in dogs with determination of quantitative measures using medium liquid and soft food boluses to minimize effects of size. Furthermore, we conclude that measurements made on liquid swallows should not be directly compared to measurements made on soft food boluses.

COMPARISON OF THE RADIOGRAPHIC AND TRACHEOSCOPIC APPEARANCE OF THE DORSAL TRACHEAL MEMBRANE IN LARGE AND SMALL BREED DOGS.

The etiology and clinical significance of increased radiographic opacity along the dorsal margin of the tracheal lumen has long been debated. Most often, this opacity is attributed to redundancy of the dorsal tracheal membrane (DTM), a condition that occurs with tracheal collapse. We hypothesized that the underlying etiology of this radiographic opacity differs between small breed dogs with tracheal collapse and small or large breed dogs without tracheal collapse. The purpose of this prospective, cross-sectional study was to compare the radiographic appearance of an increased opacity within the trachea to tracheoscopy findings in a group of small and large breed dogs. A total of 17 small breed dogs and 16 large breed dogs were included. Of these, only one did not have a radiographically visible DTM. Small breed dogs were divided into groups with tracheal collapse (n = 8) and those without (n = 9) based on tracheoscopy. Tracheal collapse was absent in larger breed dogs, however both large and small breed dogs demonstrated inward invagination of the DTM. In dogs with tracheal collapse, the DTM occupied a larger percentage of the tracheal luminal height on radiographs and a larger percentage of tracheal circumference on tracheoscopy vs. dogs with an invaginated DTM on tracheoscopy and dogs with no collapse and no invagination of the DTM. Findings supported the hypothesis that increased radiographic opacity along the dorsal margin of the trachea arises from different etiologies in dogs with and without tracheal collapse.

Prevalence of incidental thyroid nodules in ultrasound studies of dogs with hypercalcemia (2008-2013).

Ultrasound is commonly used to evaluate the cervical region in dogs with hypercalcemia due to suspected hyperparathyroidism. Incidental thyroid nodules may be detected during these studies, however little information has been published to guide clinical decision-making when this occurs. The purpose of this cross-sectional study was to determine the prevalence of incidental thyroid nodules in hypercalcemic dogs undergoing cervical ultrasound at our hospital during the period of 2008-2013. Dogs with a palpable neck mass were excluded. Cervical ultrasound images for each dog were retrieved and reviewed by a board certified veterinary radiologist who was unaware of patient outcome. Presence, number, and dimensions of thyroid nodules were recorded. Results of thyroid nodule aspirate, biopsy or necropsy were recorded from medical records when available. Ninety-one dogs met inclusion criteria. Of these, 14/91 (15%) dogs had at least one thyroid nodule. Mean (± standard deviation) thyroid gland nodule length, width, and height were 1.51 ± 0.74, 0.96 ± 0.73, and 0.75 ± 0.36 cm, respectively. A histologic diagnosis was available for the incidental thyroid lesions in eight dogs, including one dog with two nodules. Confirmed diagnoses for these nodules were thyroid cyst (3/9, 33%), thyroid adenoma (3/9, 33%), thyroid adenocarcinoma (2/9, 22%) and nodular hyperplasia (1/9, 11%). Findings indicated that incidental thyroid nodules may be present in hypercalcemic dogs with no palpable neck mass and no clinical signs of thyroid disease. Some of these nodules may be malignant and therefore a recommendation for cytology or biopsy may be justified.

Contrast videofluoroscopic assessment of dysphagic cats.

The diagnostic utility of contrast-enhanced videofluoroscopic esophagography in dysphagic cats has been rarely studied relative to dogs. Current literature regarding feline dysphagia typically consists of individual case reports or small case series. This retrospective study analyzed the imaging findings in 11 cats undergoing 15 videofluoroscopic swallow studies. Hiatal hernia (n = 5), esophageal stricture (n = 3), and esophageal dysmotility (n = 7) were the most common diagnoses (some cats having more than 1 diagnosis) in dysphagic cats that underwent videofluoroscopic swallow studies. Esophageal dysmotility appeared to be associated with a higher percentage of swallows from which no peristaltic waves were generated. Oropharyngeal and cricopharyngeal causes of dysphagia were not identified in any cat and quantitative assessment of the swallowing reflex (pharyngeal constriction ratio = 0.17 ± 0.09; time to maximum pharyngeal contraction = 0.13 ± 0.02 s; time to proximal esophageal sphincter opening = 0.07 ± 0.02 s; time to proximal esophageal sphincter closed = 0.23 ± 0.05 s; time to opening of the epiglottis = 0.27 ± 0.04 s) was similar to quantitative swallowing parameters previously reported in healthy dogs. In conclusion, videofluoroscopy is a diagnostic tool that can identify esophageal abnormalities that are not readily apparent on survey radiographs. Limitations include the potential need for multiple studies, and the possibility of poor compliance in the feline patient. Results of this study are intended to help veterinarians define a prioritized differential diagnosis list for dysphagic cats.

Radiographic characterization of primary lung tumors in 74 dogs.

Primary pulmonary neoplasia is well recognized in dogs and prognosis depends upon the tumor type. The purpose of this retrospective study was to characterize the radiographic appearance of different primary lung tumors with the goal of establishing imaging criteria to separate the different types. Three-view thoracic radiographs of 74 dogs with histologically confirmed pulmonary anaplastic carcinoma (n = 2), adenocarcinoma (n = 31), bronchioalveolar carcinoma (n = 19), histiocytic sarcoma (n = 21), and squamous cell carcinoma (n = 1) were evaluated. Radiographs were assessed for tumor volume, affected lobe, location within lobe, overall pulmonary pattern, presence of cavitation, mineralization, air bronchograms, lymphadenomegaly, and pleural fluid. Histiocytic sarcomas were significantly larger than other tumor types (271 cm(3); P = 0.009) and most likely to be found in the left cranial (38%; 8/21) and right middle (43%; 9/21) lung lobes, whereas adenocarcinomas were most likely to be found in the left caudal (29%; 9/31) lung lobe. Fifty-seven percent (12/21) of histiocytic sarcomas had an internal air bronchogram. Findings indicate that a large mass in the periphery or affecting the whole lobe of the right middle or left cranial lung lobe with an internal air bronchogram is likely to be an histiocytic sarcoma.

Effects of corn oil administered orally on conspicuity of ultrasonographic small intestinal lesions in dogs with lymphangiectasia.

Lymphangiectasia is one of the causes of protein-losing enteropathy in dogs and characteristic ultrasonographic small intestinal lesions have been previously described. The purpose of this study was to determine whether corn oil administered orally (COAO) would result in increased conspicuity of these characteristic small intestinal ultrasonographic lesions in dogs with lymphangiectasia. Affected dogs were included if they underwent corn oil administered orally and had a surgical full-thickness intestinal biopsy diagnosis of lymphangiectasia. Control dogs had normal clinical examination and standard laboratory test findings. Ultrasound images of duodenum, jejunum, and ileum were obtained prior to and 30, 60, 90, and 120 min after corn oil administered orally for all dogs. Parameters recorded for each ultrasound study were intestinal wall thickness, mucosal echogenicity, and presence or absence of hyperechoic mucosal striations (HMS) and a parallel hyperechoic mucosal line (PHML). Nine affected and five controls dogs were included in the study. Seven of the nine dogs with lymphangiectasia had hyperechoic mucosal striations prior to corn oil administered orally. Jejunal hyperechoic mucosal striations were significantly associated with lymphangiectasia at multiple time points (P < 0.05) and were best identified in dogs with lymphangiectasia 60 or 90 min after corn oil administered orally. Increased mucosal echogenicity was observed in all dogs at multiple time points after corn oil administered orally. A parallel hyperechoic mucosal line was present in the jejunum in 4/5 healthy and 6/9 dogs with lymphangiectasia at one or more time points after corn oil administered orally. Findings indicated that corn oil administered orally improves conspicuity of characteristic ultrasonographic lesions in dogs with lymphangiectasia, however some of these lesions may also be present in healthy dogs that recently received a fatty meal.

Infant rhesus macaques immunized against SARS-CoV-2 are protected against heterologous virus challenge 1 year later.

The U.S. Food and Drug Administration only gave emergency use authorization of the BNT162b2 and mRNA-1273 SARS-CoV-2 vaccines for infants 6 months and older in June 2022. Yet questions regarding the durability of vaccine efficacy, especially against emerging variants, in this age group remain. We demonstrated previously that a two-dose regimen of stabilized prefusion Washington SARS-CoV-2 S-2P spike (S) protein encoded by mRNA encapsulated in lipid nanoparticles (mRNA-LNP) or purified S-2P mixed with 3M-052, a synthetic Toll-like receptor (TLR) 7/8 agonist, in a squalene emulsion (Protein+3M-052-SE) was safe and immunogenic in infant rhesus macaques. Here, we demonstrate that broadly neutralizing and spike-binding antibodies against variants of concern (VOCs), as well as T cell responses, persisted for 12 months. At 1 year, corresponding to human toddler age, we challenged vaccinated rhesus macaques and age-matched nonvaccinated controls intranasally and intratracheally with a high dose of heterologous SARS-CoV-2 B.1.617.2 (Delta). Seven of eight control rhesus macaques exhibited severe interstitial pneumonia and high virus replication in the upper and lower respiratory tract. In contrast, vaccinated rhesus macaques had faster viral clearance with mild to no pneumonia. Neutralizing and binding antibody responses to the B.1.617.2 variant at the day of challenge correlated with lung pathology and reduced virus replication. Overall, the Protein+3M-052-SE vaccine provided superior protection to the mRNA-LNP vaccine, emphasizing opportunities for optimization of current vaccine platforms. The observed efficacy of both vaccines 1 year after vaccination supports the implementation of an early-life SARS-CoV-2 vaccine.

Corrigendum: Craniomaxillofacial Trauma in Dogs-Part I: Fracture Location, Morphology and Etiology.

[This corrects the article DOI: 10.3389/fvets.2020.00241.].

SARS-CoV-2 Infection of Rhesus Macaques Treated Early with Human COVID-19 Convalescent Plasma.

Human clinical studies investigating use of convalescent plasma (CP) for treatment of coronavirus disease 2019 (COVID-19) have produced conflicting results. Outcomes in these studies may vary at least partly due to different timing of CP administration relative to symptom onset. The mechanisms of action of CP include neutralizing antibodies but may extend beyond virus neutralization to include normalization of blood clotting and dampening of inflammation. Unresolved questions include the minimum therapeutic titer in the CP units or CP recipient as well as the optimal timing of administration. Here, we show that treatment of macaques with CP within 24 h of infection does not reduce viral shedding in nasal or lung secretions compared to controls and does not detectably improve any clinical endpoint. We also demonstrate that CP administration does not impact viral sequence diversity in vivo, although the selection of a viral sequence variant in both macaques receiving normal human plasma was suggestive of immune pressure. Our results suggest that CP, administered to medium titers, has limited efficacy, even when given very early after infection. Our findings also contribute information important for the continued development of the nonhuman primate model of COVID-19. These results should inform interpretation of clinical studies of CP in addition to providing insights useful for developing other passive immunotherapies and vaccine strategies. IMPORTANCE Antiviral treatment options for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain very limited. One treatment that was explored beginning early in the pandemic (and that is likely to be tested early in future pandemics) is plasma collected from people who have recovered from coronavirus disease 2019 (COVID-19), known as convalescent plasma (CP). We tested if CP reduces viral shedding or disease in a nonhuman primate model. Our results demonstrate that administration of CP 1 day after SARS-CoV-2 infection had no significant impact on viral loads, clinical disease, or sequence diversity, although treatment with normal human plasma resulted in selection of a specific viral variant. Our results demonstrate that passive immunization with CP, even during early infection, provided no significant benefit in a nonhuman primate model of SARS-CoV-2 infection.

Early post-infection treatment of SARS-CoV-2 infected macaques with human convalescent plasma with high neutralizing activity reduces lung inflammation.

Early in the SARS-CoV-2 pandemic, there was a high level of optimism based on observational studies and small controlled trials that treating hospitalized patients with convalescent plasma from COVID-19 survivors (CCP) would be an important immunotherapy. However, as more data from controlled trials became available, the results became disappointing, with at best moderate evidence of efficacy when CCP with high titers of neutralizing antibodies was used early in infection. To better understand the potential therapeutic efficacy of CCP, and to further validate SARS-CoV-2 infection of macaques as a reliable animal model for testing such strategies, we inoculated 12 adult rhesus macaques with SARS-CoV-2 by intratracheal and intranasal routes. One day later, 8 animals were infused with pooled human CCP with a high titer of neutralizing antibodies (RVPN NT 50 value of 3,003), while 4 control animals received normal human plasma. Animals were monitored for 7 days. Animals treated with CCP had detectable levels of antiviral antibodies after infusion. In comparison to the control animals, they had similar levels of virus replication in the upper and lower respiratory tract, but had significantly reduced interstitial pneumonia, as measured by comprehensive lung histology. By highlighting strengths and weaknesses, data of this study can help to further optimize nonhuman primate models to provide proof-of-concept of intervention strategies, and guide the future use of convalescent plasma against SARS-CoV-2 and potentially other newly emerging respiratory viruses. AUTHOR SUMMARY: The results of treating SARS-CoV-2 infected hospitalized patients with COVID-19 convalescent plasma (CCP), collected from survivors of natural infection, have been disappointing. The available data from various studies indicate at best moderate clinical benefits only when CCP with high titer of neutralizing antibodies was infused early in infection. The macaque model of SARS-CoV-2 infection can be useful to gain further insights in the value of CCP therapy. In this study, animals were infected with SARS-CoV-2 and the next day, were infused with pooled human convalescent plasma, selected to have a very high titer of neutralizing antibodies. While administration of CCP did not result in a detectable reduction in virus replication in the respiratory tract, it significantly reduced lung inflammation. These data, combined with the results of monoclonal antibody studies, emphasize the need to use products with high titers of neutralizing antibodies, and guide the future development of CCP-based therapies.