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1.
Immunity ; 55(11): 1993-2005, 2022 Nov 08.
Article in English | MEDLINE | ID: covidwho-2105131

ABSTRACT

The lipid nanoparticle (LNP)-encapsulated, nucleoside-modified mRNA platform has been used to generate safe and effective vaccines in record time against COVID-19. Here, we review the current understanding of the manner whereby mRNA vaccines induce innate immune activation and how this contributes to protective immunity. We discuss innate immune sensing of mRNA vaccines at the cellular and intracellular levels and consider the contribution of both the mRNA and the LNP components to their immunogenicity. A key message that is emerging from recent observations is that the LNP carrier acts as a powerful adjuvant for this novel vaccine platform. In this context, we highlight important gaps in understanding and discuss how new insight into the mechanisms underlying the effectiveness of mRNA-LNP vaccines may enable tailoring mRNA and carrier molecules to develop vaccines with greater effectiveness and milder adverse events in the future.


Subject(s)
COVID-19 , Humans , COVID-19/prevention & control , Vaccines, Synthetic , RNA, Messenger/genetics , Immunity, Innate
2.
Cells ; 11(21)2022 Nov 03.
Article in English | MEDLINE | ID: covidwho-2099367

ABSTRACT

The cGAS-STING pathway displays important functions in the regulation of innate and adaptive immunity following the detection of microbial and host-derived DNA. Here, we briefly summarize biological functions of STING and review recent literature highlighting its important contribution in the context of respiratory diseases. Over the last years, tremendous progress has been made in our understanding of STING activation, which has favored the development of STING agonists or antagonists with potential therapeutic benefits. Antagonists might alleviate STING-associated chronic inflammation and autoimmunity. Furthermore, pharmacological activation of STING displays strong antiviral properties, as recently shown in the context of SARS-CoV-2 infection. STING agonists also elicit potent stimulatory activities when used as an adjuvant promoting antitumor responses and vaccines efficacy.


Subject(s)
COVID-19 , Membrane Proteins , Humans , Membrane Proteins/metabolism , COVID-19/drug therapy , SARS-CoV-2 , Adaptive Immunity , Autoimmunity
3.
Pharmaceutics ; 14(10)2022 Sep 20.
Article in English | MEDLINE | ID: covidwho-2093924

ABSTRACT

Viruses, bacteria, fungi, and several other pathogenic microorganisms usually infect the host via the surface cells of respiratory mucosa. Nasal vaccination could provide a strong mucosal and systemic immunity to combat these infections. The intranasal route of vaccination offers the advantage of easy accessibility over the injection administration. Therefore, nasal immunization is considered a promising strategy for disease prevention, particularly in the case of infectious diseases of the respiratory system. The development of a nasal vaccine, particularly the strategies of adjuvant and antigens design and optimization, enabling rapid induction of protective mucosal and systemic responses against the disease. In recent times, the development of efficacious nasal vaccines with an adequate safety profile has progressed rapidly, with effective handling and overcoming of the challenges encountered during the process. In this context, the present report summarizes the most recent findings regarding the strategies used for developing nasal vaccines as an efficient alternative to conventional vaccines.

4.
Hpb ; 24(Supplement 1):S197-S198, 2022.
Article in English | EMBASE | ID: covidwho-2095426

ABSTRACT

Introduction: The Codman 3000 pump was the commonest system used in the U.S. for HAIP until 2018 device discontinuation. There are many countries abroad where Codman devices have never been available. The aim is to describe our early experience with the use of Celsite T202F B. Braun catheter-Syncromed II Medtronic pump in the first Latin American HAIP program. Method(s): We describe early outcomes of 6 patients with HAIP that used Celsite T202F, 6.5 Fr B. Braun catheter-Synchromed II Medtronic pump combination. Result(s): 2 patients were female (33.3%). Unresectable colorectal liver metastasis (CRLM) in 3 patients (50%), adjuvant chemotherapy for CRLM in 1 (16.6%) and intrahepatic cholangiocarcinoma in 2 (33.3%). No extra hepatic perfusion was documented. Complications were present in 4 patients (66.6%). 3 (50%) were not related to the hepatic pump: 1 COVID-19 pneumonia, 1 colonic anastomosis leakage and 1 intraabdominal collection. One patient (16.6%) presented a pump pocket seroma. Floxuridine was the intra arterial drug administered in all patients. The median number of cycles administered was 6. All patients have partial response to date. The median follow up was 234 days. No catheter disconnection or dysfunction events occurred. Conclusion(s): The use of the Celsite B Braun catheter-Medtronic pump is a feasible and safe option for HAIP. A HAIP program can be implemented safely in Latin-America. [Formula presented] Figure 1. Celsite T202F B. Braun catheter connection with Synchromed II Medtronic pump. Copyright © 2022

5.
Vaccines (Basel) ; 10(11)2022 Oct 31.
Article in English | MEDLINE | ID: covidwho-2090408

ABSTRACT

The Middle East respiratory syndrome (MERS) is a fatal acute viral respiratory disease caused by MERS-coronavirus (MERS-CoV) infection. To date, no vaccine has been approved for MERS-CoV despite continuing outbreaks. Inactivated vaccines are a viable option when developed using the appropriate inactivation methods and adjuvants. In this study, we evaluated the immunogenicity and protective effects of MERS-CoV vaccine candidates inactivated by three different chemical agents. MERS-CoV was effectively inactivated by formaldehyde, hydrogen peroxide, and binary ethylene imine and induced humoral and cellular immunity in mice. Although inflammatory cell infiltration was observed in the lungs four days after the challenge, the immunized hDPP4-transgenic mouse group showed 100% protection against a challenge with MERS-CoV (100 LD50). In particular, the immune response was highly stimulated by MERS-CoV inactivated with formaldehyde, and all mice survived a challenge with the minimum dose. In the adjuvant comparison test, the group immunized with inactivated MERS-CoV and AddaVax had a higher immune response than the group immunized with aluminum potassium sulfate (alum). In conclusion, our study indicates that the three methods of MERS-CoV inactivation are highly immunogenic and protective in mice and show strong potential as vaccine candidates when used with an appropriate adjuvant.

6.
Viruses ; 14(11)2022 Oct 27.
Article in English | MEDLINE | ID: covidwho-2090362

ABSTRACT

Bovine coronavirus (BCoV) causes severe diarrhea in neonatal calves, winter dysentery in adult cattle, and respiratory disease in feedlot cattle, resulting in economic losses. A total of 16/140 calf diarrheic feces samples collected in South Korea between 2017 and 2018 were positive for BCoV. Phylogenetic analysis of the complete spike and hemagglutinin/esterase genes revealed that the 16 Korean BCoV strains belonged to group GIIa along with Korean strains isolated after 2000, whereas Korean BCoV strains isolated before 2000 belonged to group GI. Mice and goats inoculated with an inactivated KBR-1 strain (isolated from this study) generated higher antibody titers (96 ± 13.49 and 73 ± 13.49, respectively) when mixed with the Montanide01 adjuvant than when mixed with the Carbopol or IMS1313 adjuvants. Viral antigens were detected in the large intestine, jejunum, and ileum of calves inoculated with inactivated KBR-1 vaccine (104.0 TCID50/mL) at 14 days of post-challenge (DPC). However, no viral antigens were detected in calves vaccinated with a higher dose of inactivated KBR-1 strain (106.0 TCID50/mL) at 14 DPC, and they had high antibody titers and stable diarrhea scores. Currently, the group GIIa is prevalent in cows in South Korea, and although further research is needed in the future, the recently isolated KBR-1 strain has potential value as a new vaccine candidate.


Subject(s)
Cattle Diseases , Coronavirus Infections , Coronavirus, Bovine , Female , Cattle , Animals , Mice , Phylogeny , Feces , Diarrhea/veterinary , Antigens, Viral , Republic of Korea
7.
J Immunol Methods ; 511: 113380, 2022 Oct 25.
Article in English | MEDLINE | ID: covidwho-2086445

ABSTRACT

The SARS-CoV-2 pandemic continues despite the presence of effective vaccines, and novel vaccine approaches may help to reduce viral spread and associated COVID-19 disease. Current vaccine administration modalities are based on systemic needle-administered immunisation which may be suboptimal for mucosal pathogens. Here we demonstrate in a mouse model that small-volume intranasal administration of purified spike (S) protein in the adjuvant polyethylenemine (PEI) elicits robust antibody responses with modest systemic neutralisation activity. Further, we test a heterologous intranasal immunisation regimen, priming with S and boosting with RBD-Fc. Our data identify small volume PEI adjuvantation as a novel platform with potential for protective mucosal vaccine development.

8.
Vaccines (Basel) ; 10(10)2022 Oct 20.
Article in English | MEDLINE | ID: covidwho-2082259

ABSTRACT

Most of the current SARS-CoV-2 vaccines are based on parenteral immunization targeting the S protein. Although protective, such vaccines could be optimized by inducing effective immune responses (neutralizing IgA responses) at the mucosal surfaces, allowing them to block the virus at the earliest stage of the infectious cycle. Herein a recombinant chimeric antigen called LTB-RBD is described, which comprises the B subunit of the heat-labile enterotoxin from E. coli and a segment of the RBD from SARS-CoV-2 (aa 439-504, carrying B and T cell epitopes) from the Wuhan sequence and the variant of concern (VOC)-delta. Since LTB is a mucosal adjuvant, targeting the GM1 receptor at the surface and facilitating antigen translocation to the submucosa, this candidate will help in designing mucosal vaccines (i.e., oral or intranasal formulations). LTB-RBD was produced in E. coli and purified to homogeneity by IMAC and IMAC-anionic exchange chromatography. The yields in terms of pure LTB-RBD were 1.2 mg per liter of culture for the Wuhan sequence and 3.5 mg per liter for the delta variant. The E. coli-made LTB-RBD induced seric IgG responses and IgA responses in the mouth and feces of mice when subcutaneously administered and intestinal and mouth IgA responses when administered nasally. The expression and purification protocols developed for LTB-RBD constitute a robust system to produce vaccine candidates against SARS-CoV-2 and its variants, offering a low-cost production system with no tags and with ease of adaptation to new variants. The E. coli-made LTB-RBD will be the basis for developing mucosal vaccine candidates capable of inducing sterilizing immunity against SARS-CoV-2.

9.
Colorectal Disease ; 24(Supplement 3):288-289, 2022.
Article in English | EMBASE | ID: covidwho-2078411

ABSTRACT

Aim: The Covid-19 pandemic has caused significant strain on the UK national healthcare system. Consequently, there has been a delay in elective colorectal cancer (CRC) resections performed across the UK. We aim to assess how a delay in surgical resection of CRC patients due to covid influences may influence tumour histology and post-operative outcomes compared to pre-pandemic period Method: Retrospective review of timing of CRC resection since diagnosis, tumour histology and post-surgical outcomes of all patients undergoing elective non-metastatic CRC resection during March to June 2020 (covid group) with that during March to June 2019 (pre-covid group) Results: 82 new CRCs were diagnosed in covid group compared to 73 in pre-covid group. In pre-covid group, 61.5% patients underwent resection <4 weeks since diagnosis, 20.2% in 4 to <8 weeks, and 13.7% in >=8 weeks. Comparatively, in covid group, 17.7% patients underwent resection <4 weeks (p = 0.019), 24.4% in 4 to <8 weeks, and 53.3% in >=8 weeks (p = 0.034). Rectal cancer resection had more notable delay >=8 weeks in covid group compared to pre-covid. 25.6% patients had confirmed T4 histology in covid group, compared to 12.3% (p = 0.035) in pre-covid. 14.9% patients received adjuvant therapy following CRC resection in pre-covid group, compared to 29.8% in covid group (p = 0.042). Surgical delays >8 weeks during pandemic were significantly associated with high tumour grade (p = 0.032). Surgical delays, however, were not statistically significantly associated with need for adjuvant therapy post-resection, 1 year disease free survival rates, or palliation rates (p > 0.1). Conclusion(s): Covid pandemic has led to significant delays in elective CRC resections. Delayed CRC resections due to covid influence were associated with advanced tumour histology, but not with worsening short-term oncological outcomes. A longer study period is required to assess whether advanced tumour histology during pandemic leads to higher rates of localised or distant recurrence.

10.
Colorectal Disease ; 24(Supplement 2):61, 2022.
Article in English | EMBASE | ID: covidwho-2078389

ABSTRACT

Purpose: To assess the impact of the COVID-19 pandemic in England on diagnoses and treatments for colorectal cancer (CRC), and evaluate the variation in deficit of diagnoses and major resections by age and deprivation Methods: Rapid Cancer Registrations Data were used, linked to Hospital Episode Statistics, the Systemic Anti-Cancer Therapy Dataset and the National Radiotherapy Dataset. 33,814 patients newly diagnosed with CRC 1 January 2019 to 31 March 2021 were included Results: There was a large deficit in new CRC diagnoses and treatments early in the pandemic. There was still an 8.6% deficit in new CRC diagnoses by March 2021, a 17.6% deficit in major resections by end 2020, a 21.9% deficit in adjuvant chemotherapy by February 2021, but little deficit in curative radiotherapy for rectal cancer by March 2021. By March 2021 those just below and just above screening age had the largest deficits of new diagnoses. The most deprived patients had the largest deficit of diagnoses and major resections (20 to 21% deficit in major resections in the two most deprived quintiles compared to 16 to 17% in the other quintiles) Conclusion(s): Ongoing efforts to promote and raise awareness of bowel cancer signs and symptoms should continue to try to mitigate the delays in bowel cancer diagnoses during the pandemic, with particular focus on the most deprived and on those just below and just above screening age. Further work is needed to understand the reasons for the association between socioeconomic deprivation and deficit in diagnoses and major resections.

11.
Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz ; 2022 Oct 18.
Article in German | MEDLINE | ID: covidwho-2075318

ABSTRACT

Currently (as of July 2022), six different COVID-19 vaccines are licensed in the EU. These include two mRNA-based vaccines (BNT162b2, Comirnaty® and mRNA-1273, Spikevax®), two adenoviral vector-based vaccines (AZD1222, Vaxzevria® and Ad26.COV2.S, Jcovden®), the subunit vaccine Nuvaxovid® (NVX-CoV2373), and the inactivated virus vaccine VLA2001. Although these vaccines are based on different technologies, they all share the use of the spike protein of SARS-CoV­2 as antigen.This overview describes the characteristics of their composition, their efficacy, and the impact of various factors on efficacy. Another aspect of this overview is the description of the approval process and the identification of factors that have contributed to the unprecedented speed in the development and approval of vaccines against a pandemic pathogen.

12.
Translational Journal of the American College of Sports Medicine ; 7(4), 2022.
Article in English | Web of Science | ID: covidwho-2070711

ABSTRACT

Introduction/Purpose Adjuvant endocrine therapy significantly improves survival in women with hormone receptor-positive breast cancer and is typically administered for 5 yr or longer. Adverse treatment side effects, including arthralgias, reduce treatment adherence and physical activity levels. Aerobic and resistance exercise is one strategy to decrease treatment side effects and improve treatment adherence. This study aimed to explore the feasibility of a virtually delivered exercise program for women receiving adjuvant endocrine therapy as part of breast cancer treatment. Methods This is a single-arm pilot study with recruitment by self-referral or oncologist referral of female breast cancer survivors. To adapt to coronavirus disease 2019 (COVID-19) restrictions, a supervised strength and aerobic group exercise program was delivered virtually twice weekly via Zoom over 6 wk. Feasibility was evaluated based on a priori targets specific to program recruitment (>30% recruitment ratio), transition to virtual delivery (>75%), attendance (>70% virtual session attendance), attrition (<30% dropout), and fidelity of group belongingness (average score >= 15 on belongingness questionnaire) at the end of the program. Physical function (30-s chair stand test), quality of life RAND Short-Form 36-item test, and medication adherence (Voils Domains of Subjective Extent of Nonadherence) were assessed at baseline and 6 wk. Results A total of 24 participants completed the program. All feasibility measures were met. Statistically significant changes were found in physical function (P < 0.001), self-reported energy/fatigue (P < 0.001), emotional well-being (P < 0.001), and pain (P = 0.01). There was also a positive trend toward improvement in patient-reported medication adherence (17%). Conclusion A 6-wk supervised strength and aerobic group exercise intervention delivered virtually was feasible and improved physical function, energy/fatigue, emotional well-being, and pain. The trend toward improvement in adherence to adjuvant endocrine therapy should be explored further. These findings provide preliminary data to inform a future appropriately powered trial on exercise and physical function using a virtual platform that has the potential for greater reach.

13.
Vaccines (Basel) ; 10(10)2022 Oct 11.
Article in English | MEDLINE | ID: covidwho-2071925

ABSTRACT

Systemically vaccinated individuals against COVID-19 and influenza may continue to support viral replication and shedding in the upper airways, contributing to the spread of infections. Thus, a vaccine regimen that enhances mucosal immunity in the respiratory mucosa is needed to prevent a pandemic. Intranasal/pulmonary (IN) vaccines can promote mucosal immunity by promoting IgA secretion at the infection site. Here, we demonstrate that an intramuscular (IM) priming-IN boosting regimen with an inactivated influenza A virus adjuvanted with the liposomal dual TLR4/7 adjuvant (Fos47) enhances systemic and local/mucosal immunity. The IN boosting with Fos47 (IN-Fos47) enhanced antigen-specific IgA secretion in the upper and lower respiratory tracts compared to the IM boosting with Fos47 (IM-Fos47). The secreted IgA induced by IN-Fos47 was also cross-reactive to multiple influenza virus strains. Antigen-specific tissue-resident memory T cells in the lung were increased after IN boosting with Fos47, indicating that IN-Fos47 established tissue-resident T cells. Furthermore, IN-Fos47 induced systemic cross-reactive IgG antibody titers comparable to those of IM-Fos47. Neither local nor systemic reactogenicity or adverse effects were observed after IN delivery of Fos47. Collectively, these results indicate that the IM/IN regimen with Fos47 is safe and provides both local and systemic anti-influenza immune responses.

14.
BIOpreparations. Prevention, Diagnosis, Treatment ; 22(2):170-186, 2022.
Article in Russian | EMBASE | ID: covidwho-2067593

ABSTRACT

The COVID-19 pandemic has exacerbated the public’s need for effective vaccines. Consequently, significant financial support has been provided to developers of a number of innovative vaccines, including the vaccines with saponin-based adjuvants. In 2021, the World Health Organisation recommended Mosquirix, the first malaria vaccine, which contains a saponin adjuvant. An anti-covid vaccine by Novavax is in the approval phase. A promising approach to vaccine development is presented by the use of virus-like immune-stimulating complexes (ISCOMs) containing saponins and by the creation of combinations of ISCOMs with antigens. The aim of the study was to develop, produce and characterise virus-like immune-stimulating complexes based on saponins of Quillaja saponaria, as well as similar saponins of Russian-sourced Polemonium caeruleum. Materials and methods: The ISCOM adjuvants, Matrix-BQ and Matrix-BP, were produced using liquid chromatography and examined using electron microscopy. Balb/c mice were immunised intraperitoneally and intramuscularly with ISCOM-antigen preparations. Afterwards, the immunised animals were challenged with the influenza virus strain, A/California/4/2009(H1N1)pdm09, adapted and lethal to mice. The serum samples were examined using haemagglutination inhibition (HI) tests. Results: The authors produced the ISCOMs containing saponins of Quillaja saponaria and Polemonium caeruleum. After one intramuscular injection of either of the ISCOM-antigen preparations with 1 µg of each of A/Brisbane/02/2018 (H1N1) pdm09, A/Kansas/14/2017 (H3N2), and B/Phuket/3073/2013 haemagglutinin antigens (HAs), HI tests detected serum antibody titres to the corresponding antigens of ≥1:40. Two intramuscular injections of the ISCOM-antigen preparation containing 50 ng of each of the HAs and Matrix-BQ resulted in a protective response. In some animals, two intraperitoneal injections of ISCOM-antigen preparations resulted in the maximum antibody titre to the A/Kansas/14/2017 (H3N2) vaccine strain of 1:20,480. Two intramuscular injections of a test preparation containing 5 µg, 1 µg, 200 ng, or 50 ng of each of the HAs and Matrix-BQ or a control preparation containing 5 µg, 1 µg, or 200 ng of each of the HAs (commercially available vaccines) to the mice that were afterwards infected with the lethal influenza strain protected the experimental animals from death. Conclusions: The ISCOM-based preparations had high immunostimulatory activity in the mouse-model study. The presented results indicate the potential of further studies of ISCOM-based preparations in terms of both vaccine and immunotherapeutic development.

15.
Archivos Venezolanos de Farmacologia y Terapeutica ; 40(9):946-952, 2021.
Article in English | EMBASE | ID: covidwho-2067022

ABSTRACT

The mortality rate estimated by the WHO worldwide for CO-VID-19 has been 5.7%, much higher than other communicable infectious diseases, so it is essential to apply a vaccine to the population to reduce the viral spread, according to the WHO there are 23 projects in clinical phase stage III, such as vaccines: ChadOx1, nCov-19, Gam-COVID-Vac, CoronaVac that show promising results in research published by The Lancet Infection Diseases journal, for which we consider correlating the three vaccines and determining which is safer, generates greater im-munogenicity and less reactogenicity in volunteer participants, for which we conducted a review bibliography and a meta-anal-ysis of high impact scientific articles, concluding that the three vaccines generate a rapid and intense immune response against SARS-CoV-2, neutralizing antibodies had elevated titers in participants at 28 days, who increased and remained stable with a second dose, although each of them have been tested in different numbers and populations, applying recombinant adenovi-ral vectors and chemically inactivated virions with adjuvant and placebo for which they are totally different but with the same purpose to generate memory antibodies against SARS-CoV-2. Copyright © 2021, Venezuelan Society of Pharmacology and Clinical and Therapeutic Pharmacology. All rights reserved.

16.
Pharmaceutics ; 14(9)2022 Aug 25.
Article in English | MEDLINE | ID: covidwho-2066322

ABSTRACT

Conventional therapies for immune-mediated diseases, including autoimmune disorders, transplant reactions, and allergies, have undergone a radical evolution in the last few decades; however, they are still not specific enough to avoid widespread immunosuppression. The idea that vaccine usage could be extended beyond its traditional immunogenic function by encompassing the ability of vaccines to induce antigen-specific tolerance may revolutionize preventive and therapeutic strategies in several clinical fields that deal with immune-mediated disorders. This approach has been supported by improved data relating to the several mechanisms involved in controlling unwanted immune responses and allowing peripheral tolerance. Given these premises, several approaches have been developed to induce peripheral tolerance against the antigens that are involved in the pathological immune response, including allergens, autoantigens, and alloantigens. Technological innovations, such as nucleic acid manipulation and the advent of micro- and nanoparticles, have further supported these novel preventive and therapeutic approaches. This review focuses on the main strategies used in the development of tolerogenic vaccines, including the technological issues used in their design and the role of "inverse adjuvants". Even though most studies are still limited to the preclinical field, the enthusiasm generated by their results has prompted some initial clinical trials, and they show great promise for the future management of immune-mediated pathological conditions.

17.
Oncologist ; 2022 Oct 11.
Article in English | MEDLINE | ID: covidwho-2062950

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19) pandemic affected millions of individuals, and patients with cancer are known to be more susceptible. Vaccines against SARS-CoV-2 have been developed and used for patients with cancer, but scarce data are available on their efficacy in patients under active anti-cancer therapies. MATERIALS AND METHODS: In this study, we semi-quantitatively measured the titers of the immunoglobulin G against the anti-spike protein subunit 1 of SARS-CoV-2 after vaccination of patients with early breast cancer undergoing concurrent chemotherapy, endocrinal or targeted non-cytotoxic treatments, and no treatments. RESULTS: Standard doses of COVID-19 vaccines provided sufficient immune responses in patients with early breast cancer, regardless of the type of anticancer therapies. However, the post-vaccination serum anti-spike antibody titers were significantly lower in the patients under cytotoxic chemotherapy. CONCLUSION: Our study emphasizes the importance of the personalized risk stratification and consideration for booster doses in more vulnerable populations.

18.
Cell Mol Immunol ; 19(11): 1279-1289, 2022 Nov.
Article in English | MEDLINE | ID: covidwho-2062197

ABSTRACT

The rapid mutation and spread of SARS-CoV-2 variants urge the development of effective mucosal vaccines to provide broad-spectrum protection against the initial infection and thereby curb the transmission potential. Here, we designed a chimeric triple-RBD immunogen, 3Ro-NC, harboring one Delta RBD and two Omicron RBDs within a novel protein scaffold. 3Ro-NC elicits potent and broad RBD-specific neutralizing immunity against SARS-CoV-2 variants of concern. Notably, intranasal immunization with 3Ro-NC plus the mucosal adjuvant KFD (3Ro-NC + KFDi.n) elicits coordinated mucosal IgA and higher neutralizing antibody specificity (closer antigenic distance) against the Omicron variant. In Omicron-challenged human ACE2 transgenic mice, 3Ro-NC + KFDi.n immunization significantly reduces the tissue pathology in the lung and lowers the viral RNA copy numbers in both the lung (85.7-fold) and the nasal turbinate (13.6-fold). Nasal virologic control is highly correlated with RBD-specific secretory IgA antibodies. Our data show that 3Ro-NC plus KFD is a promising mucosal vaccine candidate for protection against SARS-CoV-2 Omicron infection, pathology and transmission potential.


Subject(s)
COVID-19 Vaccines , COVID-19 , Animals , Humans , Mice , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/genetics , COVID-19 Vaccines/immunology , Immunity, Mucosal , Administration, Intranasal
19.
Chest ; 162(4):A1866, 2022.
Article in English | EMBASE | ID: covidwho-2060877

ABSTRACT

SESSION TITLE: Drug-Induced and Associated Critical Care Cases Posters 1 SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Interstitial pneumonitis (ILD) is inflammation of lung interstitium leading to scarring and pulmonary fibrosis. Various etiologies include idiopathic, connective tissue disorders, sarcoidosis and drug induced1. Many chemotherapy agents have been implicated in drug related ILD such as bleomycin, taxanes. However, newer chemotherapeutic drugs such as molecular agents such as anti-VEGF, anti-EGFR (panitumumab) could be causative of drug induced ILD. CASE PRESENTATION: A 75-year-old female with stage IV sigmoid colon cancer treated with surgery, adjuvant FOLFOX chemotherapy and Panitumumab. She presented to the emergency department with shortness of breath and hypoxia after known COVID-19 exposure. Initial imaging with chest radiography showed bilateral ground glass opacities. A chest CT pulmonary embolism protocol was negative for pulmonary embolism but showed bilateral ground glass opacities (GGOs) and some interstitial thickening (L>R) not typical of COVID-19 infection. She was treated with remdesivir and dexamethasone, however her oxygen requirements continued to rapidly escalate. A repeat CT chest without contrast showed bilateral asymmetric interstitial thickening and GGOs. Given persistence of CT chest abnormalities, workup for interstitial lung disease was initiated. The results include ANA titer 1:80, otherwise negative ANCA profile, rheumatoid factor, anti-CCP, Scl-70, Sjogren antibodies. Given clinical history and imaging findings, diagnosis of ILD was suspected, and she was started on solumedrol 1 mg/kg. Her oxygen requirements decreased significantly over the next 2 days, and she was discharged home on oral steroid taper and pneumocystis pneumonia prophylaxis. DISCUSSION: Panitumumab is a fully humanized monoclonal antibody against EGFR. Approved by the US Food and Drug Administration in 2006 for advanced or recurrent colorectal cancer exhibiting wild-type KRAS mutation.2 ILD is rarely reported with panitumumab monotherapy, but higher incidence when used as a combination treatment such as with FOLFOX or FOLFIRI. A Japanese post-marketing surveillance study from 2010-2015 showed an ILD incidence of 1.3% but mortality rates of 51.3%.2 EGFR is expressed on basal cells and non-cilia cells of the bronchioles and type II cells of the alveolus. EGFR mediated mechanisms are important in tissue repair.3 Therefore inhibition of this pathway has been postulated to play a role in development of ILD. Another mechanism was decreased surfactant production by type II cells in pre-clinical study.4,5 ILD secondary to Panitumumab can occur at any point during therapy and up to 1 year after administration of drug.6 The role of infectious processes, in this case, COVID-19 pneumonia, could synergistically worsen ILD presentation. CONCLUSIONS: Although the incidence of ILD is low, the mortality rate is high, therefore early recognition and treatment is associated with improved clinical outcomes. Reference #1: Mudawi D, Heyes K, Hastings R, Rivera-Ortega P, Chaudhuri N. An update on interstitial lung disease. Br J Hosp Med (Lond). Jul 2 2021;82(7):1-14. Reference #2: Osawa M, Kudoh S, Sakai F, et al. Clinical features and risk factors of panitumumab-induced interstitial lung disease: a postmarketing all-case surveillance study. Int J Clin Oncol. Dec 2015;20(6):1063-1071. Reference #3: The FASEB Journal - 2000 - Puddicombe - Involvement of the epidermal growth factor receptor in epithelial repair in asthma.pdf. DISCLOSURES: No relevant relationships by Navitha Ramesh No relevant relationships by Uba Udeh

20.
Chest ; 162(4):A1780, 2022.
Article in English | EMBASE | ID: covidwho-2060861

ABSTRACT

SESSION TITLE: Drug-Induced and Associated Critical Care Cases Posters 2 SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Lung toxicity due to antineoplastic therapy is reported with both cytotoxic and molecularly targeted agents [1]. We present one such case of lung injury induced by capecitabine. CASE PRESENTATION: A 79-year-old female with history of triple negative infiltrating duct carcinoma of the right breast (status post mastectomy and adjuvant chemotherapy with docetaxel and cyclophosphamide 3 years prior) presented to the hospital with dyspnea on exertion following her fourth cycle of capecitabine therapy for breast cancer recurrence. Patient developed nausea, vomiting, and malaise with cycles 1, 2, and 3 of capecitabine therapy with onset of severe dyspnea on exertion, cough, and hypoxia following cycle 4. Computed tomography (CT) scan of the chest on admission showed consolidative opacities in the right upper, right middle, and anterior right lower lobe along with smaller opacities in the left lung apex and small subcentimeter nodules;no pulmonary embolism. Antibiotics were given for a short duration for suspected pneumonia without improvement. Capecitabine was held on discharge. She presented again to the emergency room with worsening shortness of breath, diarrhea, fatigue, and dizziness. COVID test was negative. Chest x-ray redemonstrated patchy airspace disease involving the right apical, lateral, mid lower lung field. Oral steroids were recommended for suspected organizing pneumonia, but the patient refused due to concerns about side effects. Her hospital course was complicated by Clostridium difficile infection (treated with oral vancomycin) and left lower extremity deep venous thrombosis (treated with anticoagulation). Subsequently she followed up with pulmonology outpatient. Repeat imaging showed evolving infiltrates in the same areas with elevated aspergillus IgG level (18.0 mcg/ml) and IgE (178 kU/L) but negative galactomannan and sputum bacterial/fungal/acid fast cultures. Oral steroids were initiated with clinical and symptomatic improvement. DISCUSSION: Capecitabine is a prodrug of fluorouracil (antimetabolite). It is used as a chemotherapy agent in multiple types of cancer including breast cancer. Respiratory side effects include cough (<7%) and bronchitis (<5%). Lung injury/pneumonitis is a rare complication with only a few cases reported to date [2,3]. The timing of symptoms with chemotherapy administration and the negative infectious work-up supports capecitabine as the inciting etiology of lung injury. Withholding chemotherapy and starting systemic steroids were effective treatments in this case of chemotherapy induced lung toxicity. CONCLUSIONS: Capecitabine induced lung injury is a rare but important entity and should always be kept in mind while evaluating dyspnea in cancer patients. Reference #1: Capri G, Chang J, et al. An open-label expanded access study of lapatinib and capecitabine in patients with HER2-overexpressing locally advanced or metastatic breast cancer. Ann Oncol. 2010;21(3):474. Epub 2009 Oct 8. DOI: 10.1093/annonc/mdp373 Reference #2: C. J. Benthin, G. Allada. Capecitabine-Induced Lung Injury. American Journal of Respiratory and Critical Care Medicine 2016;193:A1653. Reference #3: Andrew K Chan, Bok A Choo, John Glaholm. Pulmonary toxicity with oxaliplatin and capecitabine/5-Fluorouracil chemotherapy: a case report and review of the literature. Onkologie. 2011;34(8-9):443-6. doi: 10.1159/000331133. Epub 2011 Aug 19. DISCLOSURES: No relevant relationships by William Karkowsky No relevant relationships by Chahat Puri No relevant relationships by Sahib Singh

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