bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combined CpG and MPL as vaccine adjuvants improve immunity and heterosubtypic protection against lethal viral challenge in single dose and prime/boost regimens
Authors: Brown Deborah M ,   Clarkson Trudeau Biomedical Scholars, Lampe Anna T 
Published: January 2023

Abstract
Current Influenza A virus (IAV) vaccines show poor efficacy, often 40–60%. A strategy to improve effectiveness of IAV vaccines is to include adjuvants to activate innate immunity. We examined the potential of combined pattern recognition receptor agonists CpG and MPL to increase IAV vaccine induced protection. When administered in a single, low dose intramuscular hemagglutinin (HA) protein vaccine, mice receiving MPL + CpG experienced less morbidity after homologous challenge compared to mice receiving single agonists. In experiments analyzing heterosubtypic protection, vaccines containing MPL delivered intramuscularly (i.m.) showed increased protection against weight loss while the addition of CpG enhanced antibody responses but not survival. To determine if MPL and CpG have combinatory effects at different sites, HA and NP were delivered with MPL i.m. while HA and NP were simultaneously delivered with CpG intranasally (i.n.). Data demonstrate that combination MPL i.m. + CpG i.n. abrogated morbidity, but did not improve survival compared to MPL + CpG i.m. Further, mice given MPL + CpG produced IgG antibodies that were cross-reactive to H1N1 virus, yet magnitude of antibody responses did not correlate with protective efficacy. Finally, comparison of MPL i.m. + CpG i.n. in a prime/boost regimen, followed by heterosubtypic challenge, showed that weight loss was significantly lowered in mice that received prime/boost vaccination compared to mice that received prime only. Higher antibody responses induced by a second dose of vaccine did not correlate with protective capacity, suggesting that antibody levels, while indicators of vaccine immunogenicity, do not directly correlate with ability to protect mice from severe disease.
Supported by Trudeau Institute and Clarkson University.
Effect of methotrexate on response to Covid-19 mRNA vaccines in patients with Autoimmune Inflammatory Rheumatic Diseases: a longitudinal study
Authors: Rus Violeta , Nguyen Vinh , Shriver Mallory , Degrezia Mary , Alhassan Eaman , Passetti Marcella , Thomas Afton , Rus Horea G 
Published: January 2023

Abstract
Humoral response to Covid-19 mRNA vaccines was assessed in 30 patients with autoimmune inflammatory rheumatic diseases (AIRD) taking methotrexate (MTX) and 22 volunteers at 8 and 24 weeks after the first vaccine. Ten patients were also followed at 2–4 weeks after the booster dose. Concentrations of neutralizing Anti-Spike and anti-RBD Ab (U/ml) were assessed using the V-PLEX Covid-19 ACE2 Neutralization kit.
At 8 weeks after vaccine, median titers of anti-Spike and anti-receptor binding domain (RBD) Ab were significantly lower in patients receiving MTX (6.2, IQR [3.1–19.87] and 5.4 [2.5–15], respectively) vs. controls (25.4, [10–89] and 22.2 [10–88]). At 24 weeks post vaccine, neutralizing antibody titers declined in both groups. Although median anti-Spike and anti-RBD Ab levels remained significantly lower in patients (1.7 [0.0–3.6] and 1.9 [0.6–2.7], respectively) vs. controls (3.8 [1.2–6.6] and 3.5 [1.5–6.3]), the magnitude of the difference decreased from 4 fold at 8 weeks to 2 fold at 24 weeks. Lower titers of anti-Spike and anti-RBD Ab were found in patients taking MTX in combination with biologics (anti-TNFs or anti-Blyss) vs. those on MTX monotherapy, although only the anti-RBD Ab levels were statistically significant (2.7 [1.6–5.8] vs. 7.6 [3.8–17.4], p=0.04). Levels of neutralizing Ab did not differ in patients that held methotrexate around vaccination compared to those who did not. One control but no patients had breakthrough Covid-19 infections. After booster dose, Ab titers increased by a highly variable amount in all patients, ranging between 1.9 – 649 fold for anti-Spike Ab and 2.1 – 29 fold for anti-RBD Ab. Further studies are needed to assess the duration of the booster vaccine protection in this population.
Supported by an ICTR grant from Univ of Maryland Sch of Medicine
RNA origami as a vaccine assembly platform to promote CD8 T Cell mediated anti-tumor immunity
Authors: Yip Theresa , Qi Xiaodong , Kollings Jack , Yan Hao , Chang Yung 
Published: January 2023

Abstract
CD8 T cell mediated immunity is critical for controlling tumor growth. However, constructing synthetic vaccines that can effectively induce this arm of the immunity has been challenging. With the advancement of nanotechnologies, various nanostructures have been explored to link antigens and adjuvants together for increased stability, lymph node delivery, cellular uptake, and activation of innate immunity, all of which may help elicit potent T cell responses against tumors. Here, we explored a self-assembling RNA origami (RNA-OG) nanostructure as a vaccine platform to assemble tumor antigens. In addition to acting as an antigen carrier, RNA-OG is an intrinsic TLR3 agonist and therefore functions as a potent adjuvant. Thus, these RNA-OG-antigen vaccines offer simultaneous delivery of antigens and adjuvants for better initiation of T-cell mediated immunity. We demonstrated enhanced antigen cross-presentation of RNA-OG-linked antigens by dendritic cells and subsequent induction of antigen-specific CD8-T cell responses. Using B16-OVA (ovalalbumin) murine melanoma tumor model, RNA-OG-OVA vaccines induced an anti-tumor immune response that contributed to long-term tumor immunity and increased survival of the animals. Overall, our data demonstrates that RNA-OG can function as a potent anti-tumor vaccine platform.
Diversity Outbred and Collaborative Cross mouse models identify and validate host genetic loci associated with Immune Checkpoint Inhibitor response
Authors: Hackett Justin , Movaheddin Nasrin , Glassbrook James E , Bross Madeline , Muñiz Maria , Dyson Gregory , Gibson Heather 
Published: January 2023

Abstract
Immune checkpoint inhibitors (ICI) for cancer therapy have improved outcomes for a variety of malignancies, however many patients fail to benefit. While tumor-intrinsic mechanisms are involved in therapy resistance, it is unclear to what extent host genetic background plays in response. To investigate this in a pre-clinical setting, we utilized C57BL/6 (B6) F1 crosses of the Diversity Outbred (DO) and Collaborative Cross (CC) mouse models. We find a wide variation in response to anti-PD-1/anti-CTLA-4 ICI in B16F0-bearing DOB6F1 mice (n=142) with ~30% showing partial response and ~13% showing complete tumor elimination. Genetic linkage analysis identified several genomic loci associated with therapeutic outcomes. Of the associated loci, the region within chromosome 13 was further validated in CC mice bearing the positive (NZO) versus negative (C57BL/6) driver genotypes. ICI response was detected in 2/3 CCB6F1 predicted responder models, with no response in predicted non-responders. This locus contains the murine prolactin family which is a known immunomodulating cytokine with association to various autoimmune disorders. To directly test whether prolactin influences ICI response rates, we implanted inbred C57BL/6 mice with subcutaneous slow-release prolactin pellets to induce mild hyperprolactinemia. Combined ICI with prolactin shows an interaction effect against B16F0, with 5/8 mice exhibiting slowed tumor growth. Analysis of CD8 infiltrates by IHC demonstrate that dual treatment of prolactin and ICI results in a significant increase of CD8 infiltrates over other groups. Collectively, this study shows that host genetics play a role in ICI response and that prolactin may be a positive regulator of ICI efficacy.
Supported by grants from NIH (R37 CA220482, T32-CA009531, P30 CA022453), the Pardee Foundation, and the DMC Foundation
Analysis of biomarkers in melanoma patients receiving ICI treatments: pre- vs post in responders and progressors
Authors: Daftarian Pirouz M , Nadine Nadine , Hushur Orkash , Dronca Roxana , Dutta Navnita , Knutson Keith L 
Published: January 2023

Abstract
Markers of immune related adverse events and response in patients treated with immune checkpoint inhibitors (ICI) may shed light into ICI resistance, T cell exhaustion and other combinatorial therapies. The elevated levels of these biomarkers have potential to predict if PD-1 or PD-1/CTLA-4 antagonist combination will be effective in a certain Melanoma patient. Therefore, it may potentially guide healthcare providers to change treatment plans. In this study, the ICI treatments we focused on were PD-1 or combination of PD-1/CTLA-4 blockades. The measurement of the biomarkers was conducted at Mayo Clinic, from serum samples obtained in 2 time points, pre-treatments and 2–3 months after the first ICI treatments. Validated IVD kits were used per manufacture’s instruction. Biomarkers could be measured using stored frozen serum samples according to the instructions on how the biomarkers will be measured. We investigated 13 biomarkers in the sera of 76 melanoma patients who received immune checkpoint therapies. The biomarkers tested were, Human ELAFIN ELISA, Human IL-18 ELISA, Reg3α + Universal kit, Anti-Nuclear Antibody Test System, FLUORO AID-1 Test for anti-mitochondrial antibodies, anti-smooth muscle antibodies and anti-parietal cell antibodies, Anti-MDA5 ELISA Kit, Anti-synthetase ELISA Skin, Antineutrophil cytoplasmic antibodies MPO-ANCA ELISA, Antineutrophil cytoplasmic antibodies PR3-ANCA ELISA, Dsg1, Dsg3 ELISA, BP180, BP230, type-VII collagen. When compared with the samples obtained before treatments, IL-18 levels significantly elevated (p value &lt; 0.0001) in post treatment samples of non-responders. Further studies are needed to confirm if elevated IL-18 contribute to the biology of resistance to ICI therapies.
Supported by MBLI
Cancer immunotherapy with oncolytic enveloped self-amplifying mRNA CARG-2020 that modulates IL-12, IL-17 and PD-L1 pathways
Authors: Wang Kepeng 
Published: January 2023

Abstract
Tumors are adept at escaping the immune response through multiple mechanisms that disrupt key processes. This is observed with immune checkpoint blockade therapies and oncolytic viral therapies that are only effective in limited numbers of cancer patients. Targeting multiple immune mechanisms may overcome therapy resistance and further improve cancer immunotherapy for humans. Here we describe the use of virus-like vesicles (VLV) for the delivery of trivalent combination cancer therapy. This high-capacity oncolytic RNA replicon vector was adapted to simultaneously and synergistically stimulate immune cell activation, inhibit an immune checkpoint pathway, and disrupt a pro-tumor pathway by co-delivering interleukin (IL)-12, short-hairpin RNA (shRNA) targeting programmed death ligand 1 (PD-L1), and a dominant-negative form of IL-17 receptor A (dn-IL17RA), respectively. This trivalent viral vector (designated CARG-2020) was injected intralesionally to subcutaneous MC38 and BNL-T3 tumors, and it eradicated large established tumors in mice. The concurrent modulation of IL-12, IL-17, and PD-L1 pathways by CARG-2020 suppressed tumor recurrence and prolonged overall survival. Treatment of primary tumors by CARG-2020 also resulted in marked inhibition of distal tumors, demonstrating a strong abscopal effect of the agent. Mechanistically, CARG-2020 potently activates Th1-armed immunity in primary tumors and the spleen, and inhibits the expression of genes related to T cell exhaustion and cancer-promoting inflammation. The ability of CARG-2020 to prevent tumor recurrence in mice and extending their survival makes it a promising candidate for use in human cancer immunotherapy.
This work is supported by a National Institute of Health/National Cancer Institute grant (NIH/NCI R01CA262430).
Studies on the Antigenic Properties of the Ultraviruses
Authors: Schultz E. W. , Gebhardt L. P. , Bullock L. T. 
Published: January 2023

Summary
Though viricidal antibodies were easily demonstrated in the sera from human and monkey poliomyelitis convalescents, no evidence could be elicited to indicate that these antibodies are related to antibacterial antibodies. The presence of complement fixing and precipitating antibodies specific for the virus could not be demonstrated even in sera from hyperimmunized poliomyelitis convalescent monkeys. On the other hand, evidence was obtained which strongly suggests that the antibodies parallel antitoxins in their behavior. Like neutral toxin-antitoxin, neutral serum-virus mixtures may be rendered infective again by dilution with physiological saline solution. Moreover, while an undiluted serum of sufficient titer may render a given quantity of virus material immediately innocuous when such a serum is diluted a certain minimum of time is required to accomplish the same result.
Chemical and Immunological Studies of the Pneumococcus
Authors: Wadsworth Augustus , Brown Rachel 
Published: January 2023

Summary
From type I pneumococcus cells a specific substance, apparently carbohydrate in nature, was isolated. Its properties and antigenic activity are described as follows: Precipitation occurred with type I antipneumococcus serum in a dilution of 1:6,000,000; also, in a dilution of 1:600,000 with type I antipneumococcus serum from which the antibodies against the specific carbohydrate of Heidelberger and Avery had been adsorbed.Complement was fixed in the presence of type I antipneumococcus rabbit serum.Protein tests were negative and carbohydrate, positive.Mice immunized with it were protected against type I pneumococcus infection.It caused fatal anaphylactic shock in guinea pigs passively sensitized with type I antipneumococcus rabbit serum; also, in guinea pigs passively sensitized with type I antipneumococcus rabbit serum from which the antibodies against the specific carbohydrate of Heidelberger and Avery had been absorbed.
Factors Conditioning the Development of the Tuberculin Type of Hypersensitivity
Authors: Dienes L. 
Published: January 2023

Summary and Conclusions
Preliminary treatment with egg-white of a series of animals, thus producing an anaphylactic sensitivieness, before infection with tubercle bacilli and subsequent treatment with egg-white according to methods known to produce a tuberculin type of reaction, apparently prevented in the majority of instances the development of tuberculin-type sensitivity. One-fifth to 0.1 mgm. of egg-white is approximately the minimal single dose required for the constant production of strong tuberculin type of sensitivity. An initial injection of a much smaller amount, however, exerts a marked influence on the effect of injections given at later periods. When successive doses are used in sensitizing the animals, or when repeated skin tests are made, either the anaphylactic or the tuberculin type of sensitivity may develop. Among the factors governing which type of sensitiveness will appear are the intervals between injections, the route of injection not only of the initial but of subsequent doses and the condition of the animal dependent on the state and degree of its infection. Repeated injections in short interval favor the development of anaphylactic type of sensitivity. If the interval after the first injection is long enough for the development of a marked grade of tuberculin type of sensitivity, consecutive injections usually increase the strength of this type of sensitivity. During the first week after intravenous infection with the R1 strain of tubercle bacilli conditions as favorable for the production of the tuberculin type of sensitiveness as those afforded by a strong local infection are not produced. If the intravenous infection is a heavy one the effect appears in contrast to be distinctly inhibitory. It seems fair to conclude that the slight generalized infection which follows a local tuberculous infection has little to do with the effects observed in locally infected guinea pigs.
Blood Grouping in Poliomyelitis
Authors: Jungeblut C. W. , Smith L. W. 
Published: January 2023

Summary and Conclusions
The incidence of blood groups in cases of paralytic poliomyelitis occurring under five years of age shows no radical deviation from the normal figures. Above that age there is a distinct diminution in B and a slight increase in O. This shift in the distribution of blood groups becomes progressively more noticeable with the advance in the age at onset, coincident with the drop in general morbidity. The largest number of deaths after five years of age occurred in individuals other than B, with a predominance of A in the five to ten year period and of O in the cases over ten years. The prevalence of poliomyelitis in different parts of the world appears, with certain exceptions, to diminish in direct proportion to the increase in group B and the decrease in groups A and O among the human races. This relative racial insusceptibility seems to occur independently of climatic factors. No more than one-third of six human convalescent sera belonging to blood group A nor more than about half of thirteen sera belonging to blood groups O and AB were capable of neutralizing the virus of poliomyelitis in vitro. On the other hand six out of seven B sera were found to possess this property. These results may be useful in pointing the way to a more judicial selection of suitable donors in the collection of convalescent sera form therapeutic purposes.
Experiments in Passive Transference of Urticarial Hypersensitiveness to Fungous Extracts
Authors: Sulzberger Marion B. 
Published: January 2023

Summary
Reagins which sensitized the skin to extracts of pathogenic fungi of the trichophyton or achorion group, did not sensitize to to oidium (monilia) extracts. This coincides with previous observations which point to the immunologic relationship of the trichophyton, achorion and microsporon fungi and their immunologic differentiation from the monilias. Three of the 7 patients used as test persons did not accept passive sensitization with these reagins. These 3 and only these had been previously infected (experimenti causa) with an achorion fungus and had received injections of trichophytin prior to their employment in my experiments.
The Rate of Antibody Formation in Monkeys Actively Immunized with Poliomyelitis Virus
Authors: Brodie Maurice 
Published: January 2023

Abstract
In a previous report (1) it was shown that active immunity was produced by skin inoculation of virus-serum combinations, or sub-infective doses of virus-containing tissue, but that the latter gave decidedly more immunity. It is proposed, therefore, to trace the onset and subsequent rate of development of immunity following: (a) a single sub-infective dose of virus containing tissue, and (b) two inoculations, administered at different in-intervals.
Although Römer and Joseph (2) claimed that only after twenty-six days were antibodies for poliomyelitis demonstrable in active immunity, Leiner and Wiesner (3) found them after seven, and in one case, two days, and Amoss (4) three and one-half days after the development of the active disease. Likewise in this laboratory (5) antibody was found in monkeys on the second day after the height of paralysis. In human beings, Netter and Levaditi (6), showed antiviral substance on the twelfth day and Flexner and Amoss (7) on the sixth day of the disease.
Agglutinins and the Conditioned Reflex
Authors: Kopeloff L. M. , Kopeloff N. , Posselt E. 
Published: January 2023

Summary
Within the limitations of the methods and materials under investigation: Rabbits subjected to a conditioning procedure accompanied by injections of Pn III vaccine failed to show a secondary rise in agglutinins as a result of the conditioning stimulus alone. This is contrary to Metalnikov's conclusions.Agglutinins were measured by Heidelberger and Kabat's microchemical nitrogen technic as well as by the usual agglutination method. Both methods demonstrated the failure to induce an increase of agglutinins as a result of the conditioning procedure employed. Because of the greater accuracy and reproductibility of Heidelberger and Kabat's method more reliance is placed upon the results obtained by their technic.
Toxic Substances in Urine and Sweat of Typhoid Fever Patients As Demonstrated by the Shwartzman Phenomenon
Authors: Stolyhwo Nik 
Published: January 2023

Abstract
In 1928 Gregory Shwartzman described for the first time a new phenomenon which consisted in the following: Rabbits received an intradermal injection of 0.25 cc. of undiluted filtrate of five-to seven-day-old broth culture of a given microörganism (preparatory factors) and then twenty-four hours later were injected intravenously with a given amount of the filtrate (reacting factors). Four to five hours after the intravenous injection, there developed severe hemorrhagic and necrotic reactions at the site of the intradermal injection.
Observations previously reported by me suggested strongly that the Shwartzman phenomenon offered an opportunity to extend our knowledge concerning the hitherto unknown rôle of B. typhosus and B. paratyphosus toxic substances in human infections. In these investigations I attempted first to determine whether substances similar to those necessary for the Shwartzman phenomenon could be discovered in patients suffering from B. typhosus and B. paratyphosus infections.
Observations on Abnormal Isoantibodies Following Transfusions
Authors: Neter Erwin 
Published: January 2023

Abstract
There can be no doubt that all human beings may be classified as belonging to one of the four blood groups of Landsteiner. However, recent investigations have shown that sub-groups exist within these four main blood groups, especially within the group A. Moreover, specific antigens can be demonstrated in red blood cells which are not at all related to the group properties A and B (e.g., factors M, N and P of Landsteiner and Levine). They can be demonstrated only by means of immunization of rabbits with human blood cells containing the respective substances. There are no corresponding normal antibodies present in human serum. Ehrlich and Moregenroth were the first to produce specific isoagglutinins in goats by means of immunization. There are a few reports in the literature concerning specific isoagglutinins in men caused by immunization. Landsteiner, Levine and Janes (1) observed abnormal agglutinins in man after blood transfusions from donors of the same group.
Carbohydrate-Containing Proteins of the Hemolytic Streptococcus
Authors: Heidelberger Michael , Kendall Forrest E. 
Published: January 2023

Summary
A modification of earlier methods is given for the microdetermination of carbohydrate in protein. Scarlatinal streptococcus protein fractions contain, in general, more carbohydrate than can be accounted for by their nucleic acid content and quite regularly give rise to anticarbohydrate as well as antiprotein when injected into rabbits. Evidence is presented that the non-nucleic acid carbohydrate of the protein fractions is chemically combined “C” substance.
General and Cerebral Anaphylaxis in the Monkey (Macacus Rhesus)
Authors: Kopeloff Nicholas , Davidoff Leo M. , Kopeloff Lenore M. 
Published: January 2023

Summary
Fatal anaphylactic shock has been produced at will in monkeys following single or multiple preparatory intravenous injections of liberal amounts of fresh undiluted egg-white and in one instance by sensitization through the gastro-intestinal route. Passive transfer of rabbit anti-egg-white serum to a single monkey resulted in anaphylactic death upon injection of antigen. Local cerebral anaphylaxis as evidenced by contralateral focal symptoms and pathologic brain changes including necrosis have been observed in sensitized monkeys upon subsequent injection of the specific antigen. The pathologic picture of fatal anaphylaxis in monkeys is markedly different from that seen in any of the usual laboratory animals.