What's New in Immunogenicity?

Explore Below to Discover What’s Happening in the Immunogenicity Field Today:

Yellow Fever Vaccine Fractional Dosing Delivered Immunization

“A new study supports the option of using reduced doses of the yellow fever vaccine to meet immunization needs during outbreaks.

These researchers found that the immunologic response to a fractional dose of the 17DD yellow fever vaccine was appropriate for a response to a yellow fever outbreak among children 2 years of age or older and among non-pregnant adults.

In 2016, the world’s yellow fever vaccine stockpile was depleted during the response to two outbreaks. Under the guidance of the World Health Organization (WHO), the local government used 20 percent of the normal dose of the 17DD vaccine, to extend the available supply to meet demand.

The 17DD vaccine, known as Stamaril, was recommended by the WHO for use in this vaccination campaign on the basis of availability, clinical trial data indicating seroresponse to fractional doses, and 5 years of batch-release data.

This study’s finding is important, given the ongoing risk of outbreaks of yellow fever virus…”

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Unique Mouse Platform for Therapeutic Monoclonal Antibody Discovery

“The endogenous V, D and J antibody gene segments in the Trianni Mouse have been replaced by computationally designed sequences. The resulting transgenic mice exhibit optimal antibody gene expression in driving expression of a complete repertoire of human variable domains.

The variable (V) gene segments in the Trianni Mouse are chimeric – mouse immunoglobulin exons are replaced by human exons while but non-coding (control) genetic elements are of murine origin.

The resulting transgenic mice produce complete human repertoires as humans while providing for wild-type-mouse-like antibody responses to challenge…”

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Immunogenicity and safety of the multicomponent meningococcal B vaccine in children and adolescents

“Stanford University researchers teamed up with Italian colleagues to perform a systematic review and meta-analysis on the immunogenicity and safety of multicomponent meningococcal serogroup B vaccine (4CMenB) in the pediatric population. By searching MEDLINE, Scopus, Embase, and ClinicalTrials.gov, the team turned up 10 randomized studies and 8 extension trials that met their inclusion criteria. The meta-analysis evaluated 4CMenB safety and efficacy against four different Neisseria meningitidis serogroup B reference strains 30 days after a primary immunization course, 30 days after the primary course plus a booster dose, at least 6 months after the primary course, and at least 6 months after a booster dose. Successful seroconversion rates 30 days after a primary course of 4CMenB ranged from 84%–92% for the four strains. At 6 months, immunogenicity remained acceptable against all three tested strains in adolescents. Among children, however, seroconversion rates fell markedly for two of the four strains (M10713 and NZ98/254)—although a booster dose propped the numbers back up. Six months after the booster, the vaccine continued to be highly effective against M10713 and 5/99 but less so against 44/76-SL and NZ98/254. The results suggest that a primary course of 4CMenB produces satisfactory immune response within 30 days, but a booster is needed to prolong the protection against M10713 in children. Moreover, the long-term immunogenicity against strain NZ98/254 is suboptimal. With few potentially vaccine-related, acute serious adverse events taking place, the vaccine was also considered safe.”

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Hiding In The Crowd: Designing Therapies To Evade Immune Detection (Using In Silico Assessment)


“Using computer modeling software and DNA sequencing, Hickling and his team are working to understand which parts of the biologic medicines are provoking an immune response. These medicines, which are made of antibodies, contain sections on their surface known as epitopes that the immune system’s T- and B-cells can recognize. ‘That’s the part of the drug that looks foreign to the immune system,’ says Hickling. ‘We’ve been focusing a lot on T-cell responses, because these cells play a strong role in the generation of anti-drug antibodies,’ he adds.

When a biotherapeutic is in its development stage, Hickling and his team use computer software to predict which parts of the molecule are most likely to appear as T-cell epitopes. ‘We then try to change them to different amino acid sequences that might not be recognized by the immune system,’ he said. But this tweaking can be a balancing act. ‘We still need the drug to bind really well to its target in the body,’ he says.

Once they’ve altered the structure of the drug molecule, they test it in human blood samples to measure the activity of immune cells. ‘This tells us that the T-cells of the immune system are responding,’ he adds.”

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Zika Virus vaccine shows significantly higher immune response with Needle-free delivery

“Over 700,000 cases of Zika virus infection have been reported in the Americas since 2015. The emergence of Zika virus has challenged the scientific community to address a relatively uncharacterized pathogen posing a substantial threat to international public health. The two DNA vaccines assessed in this study were safe and well tolerated, and both were immunogenic.  However, the greatest effects were seen with VRC5283 given in split doses via needle-free injection in the VRC 320 trial.  One hundred percent (100%) of participants who received the vaccine by needle-free injection in split doses had detectable antibody responses, produced neutralizing antibodies, and had the highest T-cell responses.”

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Biosimilar Etanercept Associated With Fewer Injection Site Reactions, Less Immunogenicity Than Reference Enbrel

“A recent research letter, published in the British Journal of Dermatology, reports that a biosimilar etanercept, SB4 (approved as Benepali in the European Union and Brenzys in The Republic of Korea, Canada, and Australia), is associated with fewer injection-site reactions (ISRs) and less immunogenicity than reference etanercept (Enbrel), while maintaining equivalent efficacy…

Discussed in the research letter is a study that showed results of therapeutic equivalence of etanercept biosimilar, SB4, and the reference etanercept, demonstrated in patients with moderate to severe rheumatoid arthritis. The study being addressed in the research letter also noted that ISRs were observed less frequently with the biosimilar compared with reference etanercept up to week 52. Results showed that 22 cases of ISRs were reported in 3.7% of patients (n = 11/299) treated with SB4, and 157 cases of ISRs were reported in 17.5% of patients (n = 52/297) taking reference etanercept. In this study, patients were treated with a 50-mg once-weekly dose, which resulted in an incidence of ISRs resulting from reference etanercept injection (17.5%) comparable to the incidence of such ISRs in previously conducted studies (19%). Researchers stated that, historically, ISRs in the use of etanercept have appeared in to be in the range of 10% to 49%, and more frequent dosing was also associated with a higher incidence of ISRs.”

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Identification of Pre-Existing Adaptive Immunity to Cas9 Proteins in Humans

“The CRISPR-Cas9 system has proven to be a powerful tool for genome editing allowing for the precise modification of specific DNA sequences within a cell. Many efforts are currently underway to use the CRISPR-Cas9 system for the therapeutic correction of human genetic diseases. The most widely used homologs of the Cas9 protein are derived from the bacteria Staphylococcus aureus (S. aureus) and Streptococcus pyogenes (S. pyogenes). Based on the fact that these two bacterial species cause infections in the human population at high frequencies, we looked for the presence of pre-existing adaptive immune responses to their respective Cas9 homologs, SaCas9 (S. aureus homolog of Cas9) and SpCas9 (S. pyogenes homolog of Cas9). To determine the presence of anti-Cas9 antibodies, we probed for the two homologs using human serum and were able to detect antibodies against both, with 79% of donors staining against SaCas9 and 65% of donors staining against SpCas9.”

Carsten Trevor CharlesworthPriyanka S DeshpandeDaniel P DeverBeruh DejeneNatalia Gomez-OspinaSruthi MantriMara Pavel-DinuJoab CamarenaKenneth IWeinbergMatthew H Porteus

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What is 'Aussie' flu and should we be worried?

“One of the strains circulating this year – H3N2 – has been dubbed Aussie flu because it is the same strain that recently caused big problems for Australia.

Australia’s 2017 flu season was the worst the country had experienced in nearly a decade.

Experts are waiting to see if similar will happen in the UK, after a recent rise in cases.”

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FDA Guidance: ANDAs for Certain Highly Purified Synthetic Peptide Drug Products That Refer to Listed Drugs of rDNA Origin

“This guidance is intended to assist potential applicants in determining when an application for a synthetic peptide drug product (synthetic peptide) that refers to a previously approved peptide drug product of recombinant deoxyribonucleic acid (rDNA) origin (peptide of rDNA origin) should be submitted as an abbreviated new drug application (ANDA) under section 505(j) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) rather than as a new drug application (NDA) under section 505(b) of the FD&C Act. Specifically, this guidance covers the following five peptide drug products: glucagon, liraglutide, nesiritide, teriparatide, and teduglutide…

The justification should include data showing that any differences in impurities between the proposed generic synthetic peptide and the RLD do not modify each of the following: the physicochemical property, biological activity, or immunogenicity risk of the product. Such data should demonstrate for each new impurity that the impurity does not contain sequences that have an increased affinity for major histocompatibility complex (MHC), known as T-cell epitopes. Further, the data should demonstrate that the proposed generic synthetic peptide does not increase the aggregation propensity or the quality of the aggregates formed, especially under stress conditions, and does not contain impurities or contaminants that produce a greater or distinct stimulation of innate immune activity as compared to the RLD. Based on the information provided, FDA may recommend that additional non-clinical immunogenicity evaluations be completed for the proposed generic synthetic peptide.”

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And from our Blog!

Adalimumab biosimilar safe, effective in RA

“Patients with rheumatoid arthritis who were treated with SB5, an adalimumab biosimilar, demonstrated a comparable response rate to those who received adalimumab, as judged by the American College of Rheumatology 20% improvement criteria, according to findings published in Arthritis and Rheumatology

‘The findings from this phase 3 multicenter, randomized, double-blind, parallel-group study showed equivalent efficacy between SB5 and the [adalimumab] reference product, as demonstrated by the ACR20 response rates at week 24 and other secondary efficacy end points at week 24,” Weinblatt and colleagues wrote. “SB5 was well-tolerated and possessed [pharmacokinetics], safety and immunogenicity profiles comparable to those of the reference [adalimumab].'”

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High-Dose Cholera Vaccine Developed by UMSOM Scientists Shows Promise for Controlling Outbreaks

“Each year there are more than three million cases of cholera worldwide, a disease transmitted through contaminated food and water that hits developing countries particularly hard. While the standard regimen for protecting against cholera with existing non-living oral cholera vaccines includes administering two doses over a two-week period, research at the University of Maryland School of Medicine (UMSOM) now shows that giving a stronger single-dose of a live oral vaccine could be an effective tool in controlling outbreaks more quickly…

The vaccine, named Vaxchora, is a single-dose, live-attenuated oral vaccine. It was approved in 2016 by the Food and Drug Administration  (FDA) for use in U.S. adults 18-64 years old traveling to regions where cholera is common. PaxVax, a global biotechnology company based in California, received marketing approval from the FDA for the vaccine, and CVD scientists have been working closely with PaxVax since 2009 to develop the vaccine and secure FDA licensure approval.”

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Identification of a Tolerogenic Factor V Peptide and Its Potential Role in FVIII Tolerance Induction

“Inhibitory Anti-Drug Antibody (ADA) responses interfere with FVIII replacement efficacy in 25-30% of Hemophilia A (HA), greatly increasing patient morbidity and treatment costs. As an extension of previous work on tolerance-inducing peptides in IgG (Tregitopes) we investigated whether there were peptides in other ubiquitous serum proteins that could have high homology to peptides found in Factor VIII. We hypothesized that tolerance to cross-conserved peptides in other prevalent proteins might explain why anti-FVIII antibodies fail to develop in some severely FVIII-deficient HA patients. Using advanced computational modeling tools, we discovered in Factor V a potent regulatory peptide (FV1) with an immunologic profile (HLA and TCR binding) that is homologous to a non-identical peptide in FVIII. We postulated that treatment with a FV1-peptide containing biologic may be able to invoke tolerance to Factor VIII in patients who have anti-FVIII antibodies (Figure 1).

Our preliminary studies support this hypothesis. We developed an ex vivo assay using human PBMC (peripheral blood mononuclear cells) in which the recall response to tetanus toxoid, a well-known immunogenic protein for which there is a T memory response, was found to be robust and strongly inhibited by FV1 but not by other FV peptides. Other FV peptides with similar HLA-binding properties did not suppress tetanus toxoid response.”

Guillen, E., Rosenberg, A., Lelias, S., Hindocha, P., Terry, F., Martin, W., & De Groot, A. (2017)Identification of a Tolerogenic Factor V Peptide and Its Potential Role in FVIII Tolerance InductionBlood, 130(Suppl 1)2347.Accessed January 05, 2018. Retrieved from http://www.bloodjournal.org/content/130/Suppl_1/2347.

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FDA approves Ixifi, third Remicade biosimilar

“The FDA has approved the infliximab biosimilar Ixifi as a treatment for patients with rheumatoid arthritis, Crohn’s disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis and plaque psoriasis…

The FDA based its approval on data from the phase 3 REFLECTIONS B537-02 trial, which evaluated the safety, efficacy and immunogenicity of Ixifi vs. Remicade in combination with methotrexate among patients with moderate to severely active rheumatoid arthritis who had an inadequate response to methotrexate treatment alone.”

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Dengue ‘Achilles heel’ insight offers hope for better vaccines

“Researchers have new insights into how protective antibodies attack dengue viruses, which could lead to more effective dengue fever vaccines and drug therapies.

The University of Queensland and China’s ZhuJiang Hospital collaboratively led the study which identified an antibody that binds to, and kills, all four types of dengue virus.

The study also revealed the structural basis of the antibody binding to individual dengue viruses.

Dr Daniel Watterson, joint first author of the paper with Dr Jie Li, said that the antibody can block entry to the host cell, an essential step in the virus lifecycle.

‘As it recognises all four dengue virus types, it provides the basis of a safe and broad-spectrum anti-dengue therapy as well as informing the next generation of dengue vaccines,’ he said.”

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Guidelines say no special precautions needed for flu shots for people allergic to eggs

“For years, people with an egg allergy have been told to avoid or take special precautions when getting a flu shot because most influenza vaccines are grown in eggs and contain a tiny amount of egg protein. An updated practice parameter from the Joint Task Force on Practice Parameters stresses that people with egg allergy should receive their yearly flu shot, and that no special precautions are required. The guidelines are published in Annals of Allergy, Asthma and Immunology, the scientific journal of the American College of Allergy, Asthma and Immunology (ACAAI)…

There have been dozens of studies involving thousands of patients with egg allergy who have received a flu shot without allergic reactions – including hundreds with life-threatening egg allergy. This is because the influenza vaccine does not contain enough egg protein to cause an allergic reaction, even in patients with severe egg allergy. Prior practice parameters noted this and recommended that egg allergic patients could safely receive their vaccination at an allergist’s office. ”

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EMA: Guideline on Immunogenicity Assessment of Therapeutic Proteins

“The number of proteins used as therapeutic agents is steadily increasing. In general, most adverse
effects of therapeutic proteins are related to their pharmacological effects. One exception is the
capability of inducing unwanted immune responses. This document is a revision of the Guideline on
Immunogenicity assessment of biotechnology-derived therapeutic proteins
(EMEA/CHMP/BMWP/14327/2006) on the basis of experience from marketing authorisation applications,
scientific advices, and other new information. It includes, among others, more specific guidance for
assays for immunogenicity, and integrated analysis of the clinical significance of immunogenicity…

However, ongoing consideration should be given to the use of emerging technologies (novel in silico, in
vitro and in vivo models), which might be used as tools during development or for a first estimation of
risk for clinical immunogenicity. In vitro assays based on innate and adaptive immune cells could be
helpful in revealing cell-mediated responses.”

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