ABO blood group and COVID-19: a review on behalf of the ISBT COVID-19 working group

Authors: the ISBT COVID-19 Working Group School of Medicine


Growing evidence suggests that ABO blood group may play a role in the immunopathogenesis of SARS-CoV-2 infection, with group O individuals less likely to test positive and group A conferring a higher susceptibility to infection and propensity to severe disease. The level of evidence supporting an association between ABO type and SARS-CoV-2/COVID-19 ranges from small observational studies, to genome-wide-association-analyses and country-level meta-regression analyses. ABO blood group antigens are oligosaccharides expressed on red cells and other tissues (notably endothelium). There are several hypotheses to explain the differences in SARS-CoV-2 infection by ABO type. For example, anti-A and/or anti-B antibodies (e.g. present in group O individuals) could bind to corresponding antigens on the viral envelope and contribute to viral neutralization, thereby preventing target cell infection. The SARS-CoV-2 virus and SARS-CoV spike (S) proteins may be bound by anti-A isoagglutinins (e.g. present in group O and group B individuals), which may block interactions between virus and angiotensin-converting-enzyme-2-receptor, thereby preventing entry into lung epithelial cells. ABO type-associated variations in angiotensin-converting enzyme-1 activity and levels of von Willebrand factor (VWF) and factor VIII could also influence adverse outcomes, notably in group A individuals who express high VWF levels. In conclusion, group O may be associated with a lower risk of SARS-CoV-2 infection and group A may be associated with a higher risk of SARS-CoV-2 infection along with severe disease. However, prospective and mechanistic studies are needed to verify several of the proposed associations. Based on the strength of available studies, there are insufficient data for guiding policy in this regard.

For More Information: https://jhu.pure.elsevier.com/en/publications/abo-blood-group-and-covid-19-a-review-on-behalf-of-the-isbt-covid

Trained Innate Immunity, Epigenetics, and Covid-19

Authors: Alberto Mantovani, M.D., and Mihai G. Netea, M.D.

Innate immunity is mediated by different cell types and cell-associated or fluid-phase pattern-recognition molecules and plays a key role in tissue repair and resistance against pathogens.1 Exposure to selected vaccines, such as bacille Calmette–Guérin (BCG) or microbial components, can increase the baseline tone of innate immunity and trigger pathogen-agnostic antimicrobial resistance (known as trained innate immunity). Such training is directly relevant to resistance against infectious diseases, including Covid-19. A recent study by de Laval et al.2 pinpoints a driver of durable innate immune memory conferred by myeloid cells (monocytes, macrophages, and neutrophils).

Myeloid cells are central players in innate immunity: they produce effector molecules and contribute to the activation, orientation, and regulation of adaptive immune responses. Diversity and plasticity are fundamental properties of myeloid cells, particularly macrophages. To some extent, these properties are imprinted through ontogenetic origin (embryonal vs. adult bone marrow), but they are also influenced by environmental cues in the tissue. Moreover, in response to microbial molecules, metabolic products, or cytokines, macrophages increase effector function (“activation”), are primed for short-term responses (“priming”), or become unresponsive (“tolerance”). Microbial components can also cause long-term imprinting (“training”) of innate immunity and myeloid-cell function (Figure 1).3 (This type of imprinting is distinct from genomic imprinting whereby methyl groups are added to DNA in or near specific genes.)

For More Information: https://www.nejm.org/doi/10.1056/NEJMcibr2011679

Good news: Mild COVID-19 induces lasting antibody protection

People who have had mild illness develop antibodyproducing cells that can last lifetime

Authors: by Tamara Bhandari•May 24, 2021

Months after recovering from mild cases of COVID-19, people still have immune cells in their body pumping out antibodies against the virus that causes COVID-19, according to a study from researchers at Washington University School of Medicine in St. Louis. Such cells could persist for a lifetime, churning out antibodies all the while.

The findings, published May 24 in the journal Nature, suggest that mild cases of COVID-19 leave those infected with lasting antibody protection and that repeated bouts of illness are likely to be uncommon.

“Last fall, there were reports that antibodies wane quickly after infection with the virus that causes COVID-19, and mainstream media interpreted that to mean that immunity was not long-lived,” said senior author Ali Ellebedy, PhD, an associate professor of pathology & immunology, of medicine and of molecular microbiology. “But that’s a misinterpretation of the data. It’s normal for antibody levels to go down after acute infection, but they don’t go down to zero; they plateau. Here, we found antibody-producing cells in people 11 months after first symptoms. These cells will live and produce antibodies for the rest of people’s lives. That’s strong evidence for long-lasting immunity.”

For More Information: https://medicine.wustl.edu/news/good-news-mild-covid-19-induces-lasting-antibody-protection/

COVID-19 Science Update released: June 4, 2021 Edition 92

Authors: From the Office of the Chief Medical Officer, CDC COVID-19 Response, and the CDC Library, Atlanta GA. Intended for use by public health professionals responding to the COVID-19 pandemic.


Safety, immunogenicity, and efficacy of the BNT162b2 COVID-19 vaccine in adolescents.external icon Frenck et al. NEJM (May 27, 2021).

Key findings:

  • Vaccine efficacy was 100% (95% CI 75.3%-100%) in 12- to 15-year-olds.
    • There were no cases in the vaccinated group compared with 16 cases among the placebo group, 7 or more days after dose 2.
  • Compared with baseline, geometric mean neutralizing antibody titers were 118.3-fold higher 1 month after dose 2.
  • Vaccine reactions were mainly transient, mild to moderate, and similar to a comparator group of 16–25-year-olds.
    • Injection-site pain was reported by 79% to 86%, fatigue was reported by 60% to 66%, and headache was reported by 55% to 65% of participants (Figure).

Methods: A randomized, placebo-controlled, observer-blinded trial of Pfizer/BioNTech BNT162b2 in 2,260 adolescents 12–15 years old (1,129 received placebo). Efficacy of the vaccine was assessed based on confirmed SARS-CoV-2 infection with onset 7 or more days after dose 2. Reactogenicity events (assessed for 7 days after each dose) and unsolicited adverse events compared with 16–25 age group (n = 3,610). SARS-CoV-2 serum neutralization assays were performed. LimitationsRacial and ethnic diversity of participants 12-15 years does not reflect the general US population; short (1 month) post-vaccination safety evaluation.

Implications: Vaccination of adolescents with BNT162b2 was safe and effective. Vaccinating adolescents will broaden community protection, and it will likely facilitate reintegration into society and resumption of in-person learning.

Figure:Graphs showing systemic events with 7 days after dose 1 or dose 2 of vaccine or placeboresize iconView Larger

Note: Adapted from Frenck et al. Systemic events reported within 7 days after receiving dose 1 (top) or dose 2 (bottom) of vaccine or placebo. 1 participant in the 12-to-15-year-old group had a fever with a temperature >40°C after dose 1. From the New England Journal of Medicine, Frenck et al., Safety, immunogenicity, and efficacy of the BNT162b2 COVID-19 vaccine in adolescents. May 27, 2021, online ahead of print. Copyright © 2021 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Occurrence of severe COVID-19 in vaccinated transplant patientsexternal icon. Caillard et al. Kidney International. (May 21, 2021).

Key findings:

  • 55 solid organ transplant recipients developed COVID-19 after receiving 2 doses of mRNA vaccine.
    • Symptoms began a median of 22 days after the second vaccine dose (Figure).
    • 15 cases required hospitalization; of these, 6 were admitted to an intensive care unit, and 3 died.
  • Of 25 patients with post-vaccination serology, 24 were antibody negative; 1 was antibody positive but had low titers.

For More Information: https://www.cdc.gov/library/covid19/06042021_covidupdate.html

Pros and Cons of Adenovirus-Based SARS-CoV-2 Vaccines

Authors: Eric J. Kremer1,∗

Main Text

Most of us might be surprised by the rudimentary scientific rationale prevalent in the field of vaccine research just 50 years ago. For over a century after Louis Pasteur’s vaccine against rabies, approaches usually consisted of inactivating a virus, injecting it, and seeing if it protected the host. Unlike today, interactions between vaccinologists and immunologists to improve vaccine efficacy were marginal.

With the rise of molecular biology, vaccine designs became more nuanced and the use of viral vectors emerged. An example is the evolution and checkered history of vaccines based on adenoviruses (Ads). Live Ad types 4 (Ad4) and 7 (Ad7) have been used in North American military recruits since the 1950s to prevent severe respiratory illness.1 Similarly, dogs in western countries are vaccinated with an attenuated canine Ad type 2 (CAV-2) to prevent infection of the more virulent CAV-1.

Many of the first replication-defective Ad “vectors” in the early 1980s were vaccines. The original Ad vaccine design was relatively simple: delete a region of the viral genome that the virus needs to propagate, provide these functions via transcomplementing cells (e.g., Frank Graham’s 293 cells) so that one could grow the vaccine, and then insert into the virus genome an expression cassette encoding the targeted epitopes.

Fast forward to 2020. The SARS-CoV-2 pandemic may be headed toward historic proportions—although still far from the 1918 Spanish flu (50 million deaths) and AIDS (35 million deaths)—inflicting havoc on families, communities, and economies and overwhelming health care facilities. Clearly, we need a vaccine. Are Ad-based vaccines targeting the SARS-CoV-2 spike and capsid proteins our best bet? After almost 70 years of working with Ads, their biochemical properties are well characterized: Ads are simple to make (in ∼2 weeks a graduate student could generate enough of a novel Ad vaccine to treat a thousand mice and dozens of monkeys), easy to purify to high titer, genetically stable, easily stockpiled, relatively inexpensive, and can be delivered via aerosol, oral, intradermal, and intramuscular routes. The aerosol route is particularly relevant when targeting a respiratory virus because inducing protective immune responses that home to the tissue where infections will occur is strategically important. It is also worth noting that Ad-based vaccines tend to induce B cell and T cell responses.

Hundreds of millions of euros, dollars, and yen have been invested in advancing Ad-based vaccines. These advances include production and purification methods, genetic incorporation of epitopes into the capsid so that mononuclear phagocytes present these antigens via major histocompatibility complex (MHC) class I and II pathways, cloaking the capsid with polymers/shields or using Ad types with a lower level of seroprevalence to prevent neutralization by antibodies (NAbs) to common types found in many individuals, retargeting the vector to professional antigen-presenting cells, using helper-dependent vectors (so that the vector-infected cell only expresses the target epitopes and not Ad antigens), and single-cycle replication of vaccines to produce massive amounts of antigens. Each tweak, alone or in combination with others, has improved vaccine efficacy in preclinical trials.

As SARS-CoV-2 became a pandemic, it is astonishing that, in the case of the Ad-based vaccine frontrunners, little has changed from the basic design of 40 years ago. Some used the well-trodden path of an Ad5-based vaccine, while others switched to human (e.g., Ad26) or simian (monkey and gorilla) Ads that have low seroprevalence in Europe and North America (but not necessarily in Africa or Asia).2 Conceptually, Ad type switching to avoid NAbs is at least 30 years old. The advent of simian Ad vaccines was not developed following a rigorous testing of all of the >200 different Ad types but was most likely the result of intellectual property issues and the ability to produce simian Ads in good manufacturing practice (GMP)-compliant cells. One presumes that subsequent rounds of Ad-based coronavirus disease 2019 (COVID-19) vaccine candidates will be more sophisticated.

Should we go “all in” on an Ad-based vaccine against SARS-CoV-2? The first issue is safety. There are few drugs or biologicals that do not have side effects or cause adverse reactions. Weighing the advantages versus disadvantages during the current pandemic can be idiosyncratic, and the strength of the reasoning varies by population, culture, religious beliefs, and bizarrely (for those of us outside the USA) even political affiliation. Current criteria limit the window to identify adverse reactions to 2 months. In addition to swelling and pain at the injection site, common to some vaccines, Ad-based vaccine adverse effects include fever, pneumonia, diarrhea, transient neutropenia and lymphopenia, fatigue, labored breathing, headaches, liver damage, and fasting hyperglycaemia. Rare but grave adverse reactions include neuropathies such as Bell’s palsy, Guillain-Barré syndrome, gait disturbance, and transverse myelitis, an inflammatory condition in the spinal cord.

For More Information: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546260/

Complement control for COVID-19

Authors: Markus Bosmann1,2,3,4,*

The complement system is an integral part of innate immune defense. It consists of about 50 proteins in plasma, on cell surfaces, and inside host cells. The traditional view is that complement proteins guard the local extracellular spaces and systemic bloodstream against invading pathogens. Loss-of-function mutations resulting in terminal complement pathway deficiencies are associated with a 10,000-fold higher risk for life-threatening meningococcal infections in humans. Surprisingly, the complement system is redundant for defense against most pathogens except encapsulated bacteria. Recent concepts embrace the view that complement factors mediate functions inside cells either directly or through surface receptors. Complement activity fine-tunes homeostasis, metabolism, and biogenesis. On the other hand, uncontrolled complement activation causes disease and can even worsen the outcome of infections. Toxic complement effectors mediate tissue destruction and organ injury during inflammatory diseases. Acute respiratory distress syndrome (ARDS) and sepsis are frequent and severe complications of acute infections and notorious for excessive complement consumption. The three pathways of complement activation are designed for immune sensing of nonself surfaces and foreign antigens. The mannose-binding lectin (MBL)/ficolin pathway starts with soluble pathogen pattern recognition receptors as sensors for foreign carbohydrate motifs (Fig. 1). The alternative pathway is fueled by a spontaneous “smoldering” hydrolysis of C3 targeting all surfaces, unless these surfaces present complement inhibitory proteins (CD46, CD55, and CD59) as a protective self-signal. This C3 “tick-over” is sustained by the high concentrations of C3 in plasma (1 to 2 g/liter), the highest level of all complement factors. The classical pathway is initiated by antigen-antibody complexes that are recognized by the multimeric C1 complex. As a safeguard, IgG antibodies bound in clusters or pentameric IgM are required to surpass the activation threshold. All complement pathways converge on C3 convertase complexes leading to C3 cleavage into the larger C3b and the smaller anaphylactic C3a peptides. C3b is essential for the formation of C5 convertase for cleavage of C5 into C5b and the anaphylatoxin C5a. C5b is the starting point of the pore-forming membrane attack complex (MAC) consisting of C5b-C9 with a channel diameter of ~100 Å. The C3/C5 hub represents a gigantic amplification loop. The alternative C3bBb convertase (half-life of ~3 min) cleaves additional C3, resulting in more C3bBb and so on and so forth. This enzymatic chain reaction can deposit millions of C3b molecules on target surfaces in a few seconds. It is no surprise that such explosive events need to be tightly regulated to maintain the delicate balance of effective and justified pathogen attack, while avoiding damage of innocent bystander cells.

For More Information: https://immunology.sciencemag.org/content/6/59/eabj1014.full