Year 2020 will enter the history books described as unprecedented, remarkable, extraordinary, or once-in-a lifetime challenge for humanity.  All of us suffered from the restrictions introduced to suppress viral transmission. Many of us had loved ones affected or lost to COVID. Scientist lacked opportunities to meet, discuss and debate the scientific progress in person. The community of immunogenetics and histocompatibility professionals could not gather for their ASHI, EFI and APHIA and national society meetings. While organizers successfully moved these events online and scientists shared their results successfully, most of us had the feeling of missing the personal interactions, which are so fundamental to humans.

However, the superlatives will not only describe the challenges that we have faced but also the unprecedented scientific progress. The first COVID-19 vaccine clinical trial began just sixty-six days after the publication of the viral genome on Jan. 10, 2020. Soon thereafter, the second, third and multiple more vaccine clinical trials followed leading to emergency authorization of three different vaccines by December 2020. As the year was coming to an end, Israel was leading vaccine deployment by inoculating 9% of its population. In contrast, the normal vaccine development takes up to fifteen years. The mumps vaccine developed in 1967 was the previous record with just four years in development.

The speed of progress was only one aspect of the vaccine accomplishments. The first two authorized vaccines are mRNA vaccines, which represent a novel, previously unproven concept. The mRNA vaccines were designed in silico without having access to the virus itself but still resulted in 90 to 95% efficacy in clinical trials. These achievements were made possible by the discoveries and advances in our understanding of molecular immunology in the last decades. The incorporation of modified nucleosides in mRNA developed by Katalin Kariko and Drew Weismann that forms the basis of the new mRNA vaccines dates back to 2005. The application of these principles successfully in vaccine development has important implications. Translational medicine has always been an experimental science, where human clinical trials often do not support the expectations established by in vitro or animal studies. The remarkable success of mRNA vaccines proves that our understanding of the immune system reached a tipping point. Our theoretical expectations not only held up in animal studies but confirmed the most optimistic expectations of vaccine efficacy in human clinical trials. At such a tipping point of molecular immunology, scientific progress is expected to accelerate. Since HLA plays a key role in molecular immunology, the importance of immunogenetics will increase as well. The first reported potential side effects of the vaccine include allergic and autoimmune reactions, which have a good chance of being associated with specific HLA alleles. HLA will most likely contribute to the understanding of the diverse clinical manifestation of COVID-19.

The COVID-19 vaccine is the jewel in the crown of molecular immunology but not the only accomplishment. As 2020 is giving way to 2021, we are not only closing a year of remarkable success, but an entire decade of significant advances of molecular immunology. The mRNA vaccine concept was first commercially introduced for cancer immunotherapy for personalized vaccines developed against neoantigens present in cancer cells. Immunogenetics, specifically HLA allele diversity plays a key role in selecting the most immunogenic antigens that forms the basis for the personalized mRNA vaccine therapy. Immunogenetics also play a key role in a different kind of immunotherapy: checkpoint inhibitors. This therapy is based on the discovery of inhibition of negative immune regulation, which earned the Nobel Prize for James P. Allison and Tasuku Honjo. The U.S. Food and Drug Administration granted its first ever tissue or site-agnostic approval for pembrolizumab (anti-PD-1 antibody) for patients with high mutation burden. Since then, evidence is increasing that HLA-neoantigen interaction plays a key role in determining therapeutic response.

As 2021 begins, we expect not only a new year but a new decade of significant advances in immunology to follow with important implications for histocompatibility and immunogenetics. I personally expect significant advances in personalizing therapeutic choices for cancer patients based on their HLA genotypes and their cancer neoantigens. The clinical demonstration of how HLA alleles influence outcome of cancer immunotherapies have already been established.  The translation of these principles into therapy management will be implemented in the coming year and decade.

Patients with hematological cancers will have significantly increased choices of therapies and current therapies can be applied with significantly more precision. One of the greatest achievements of the field of HLA genotyping in the last decade is the significant improvement in survival of stem cell therapy recipients. The appearance of NGS technologies of the last decade, where Omixon played a pioneering role, has improved HLA-based matching to ultra-high resolution resulting in improved patient survival. However, the next decade will start moving into the direction of smart mismatching. The first fifty years of allogenic cell transplantation had the goals of best genetic matching between patient and donor to prevent GvHD. The next decade will move to the direction of optimizing graft versus tumor effect. As a consequence, more research will be done on the role of minor HLA alleles and the repertoire of genes included in our tests will continue to increase. Eventually, the field needs to move from allele-based rules to analyzing retrospective data by artificial intelligence. Eventually newly discovered associations will establish new ways to improve therapeutic outcome and eventually lead to proving their clinical utility.

The next decade will benefit from the advances of genetic and cellular engineering. Some of the allogenic therapies will become available as genetically engineered off-the shelf products. Some immunogenetic constraints will be eliminated by engineering out their T-cell receptors and make HLA matching unnecessary. However, these therapies will present new challenges for immunogenetics laboratories which we may not even foresee today.

Some of the technological advances in testing will also enable to make new impact. Moving from allele-based matching to epitopes will fundamentally change solid organ transplant practices. Especially deceased donor organ allocation will improve as a result of epitope-based virtual crossmatch. The fundamental enabling technology will be fast, high resolution genotyping. All these advances will improve transplant outcomes and increase the importance of HLA and immunogenetics. As HLA becomes critical in cancer care and other new indications, HLA genotyping will go towards the importance of blood typing. As a wild prediction for the end of the decade, every newborn will be HLA genotyped at birth in countries that can afford it. I look forward to seeing significant advances in histocompatibility and immunogenetics in 2021 and beyond.

 

I wish all our customers, collaborators a happy and prosperous new year!
Dr. Attila Bérces, CEO