By Michael Austin Stack, postbac in the Immune Deficiency Genetics Diseases section of the Laboratory of Clinical Immunology & Microbiology (LCIM) and Sydnee Gould, postbac in the T-Lymphocyte Biology Section of the Laboratory of Parasitic Diseases (LPD)
The NIAID Summer Journal Club launched in 2021 to provide a space for summer interns and postbacs to come together with NIAID postdocs to discuss recent scientific literature relevant to their NIAID research training. Under extraordinary circumstances, they met weekly (albeit virtually) to learn how to strategically read scientific literature and critically evaluate the findings. Research topics included infectious diseases, allergy, immunology, and research disciplines and approaches (e.g., vector biology, diagnostics, vaccines, medical countermeasure to prevent and treat disease). Two NIAID postbacs summarized the sessions in the latest edition of “In Case You Missed It” to showcase the wide and varied learning opportunities for NIAID fellows.
Thank you to the 2021 summer journal club postdoc moderators: Bruna Djeunang Dongho, Ph.D.; Joe Doehl, Ph.D.; Tamara Haque, Ph.D.; Kaneemozhe Harichandran, Ph.D.; Siddharth Krishnamurthy, Ph.D.; Flavio Matassoli, Ph.D.; Christine Schneider Lewis, Ph.D.; Malcolm Sim, Ph.D.
Vaccine Development & Medical Countermeasures
The Expanding Presence of mRNA Vaccines in Emergency Response
By Sydnee Gould, LPD
During the COVID-19 pandemic, many technologies previously under development took center stage in the efforts against the spreading virus. One such prominent, medical countermeasure effort is mRNA vaccines. Vaccines provide the body with a non-infectious component of the pathogen, allowing the body to respond and create memory immune cells for future exposures. Unlike other vaccines, mRNA vaccines do not contain proteins. mRNA is the transcript of DNA that is later turned into proteins. One of the uphill battles that researchers have fought while developing mRNA vaccines is how to stop its degradation in the cell before it can initiate a sufficient immune response.
Trainees read a publication from a Phase I influenza vaccine clinical trial in which the participants were given vaccines composed of various conserved and non-conserved protein-based parts of the influenza virus. Ultimately, vaccines composed of proteins from parts of the virus that mutated less often (i.e., conserved parts) created antibodies that effectively targeted multiple strains of the flu. Additionally, antibodies were present in participants over a year after the vaccinations were given, providing evidence of not just the effectiveness of vaccines targeting conserved proteins but also the longevity of cell memory.
- mRNA vaccines have been difficult to develop due to the protective nature of the immune system.
- mRNA vaccine technology holds great promise for future therapeutics.
- Ongoing studies of the current COVID-19 mRNA vaccines will contribute heavily toward progressing the field forward.
Articles: The promise of mRNA vaccines: a biotech and industrial perspective; A chimeric hemagglutinin-based universal influenza virus vaccine approach induces broad and long-lasting immunity in a randomized, placebo-controlled phase I trial
T-Cell Memory Contributes to Novel Pathogen Invasion
By Sydnee Gould, LPD
COVID-19 has allowed researchers to study host reactivity to a novel pathogen. Their research has provided insight into the complex but essential functions of a T cell. In an immune response, the invading pathogen triggers a host reaction when T cells bind to foreign antigen. These bound T cells become activated, divide, and respond by recruiting additional immune cells to the area, secreting inflammatory signals, or directly killing pathogens. Everyone has a unique repertoire of T cells with different receptors for various pathogens. It was previously thought that novel pathogens activate naive T cells—T cells that have never seen antigen. However, recent studies in COVID-19 patients have found that memory T cells can also be involved in mounting a defense against a new invader in instances where there is cross-reactivity. Cross-reactivity occurs when the memory cell is specific for a previous pathogen but is also able to bind to a new pathogen. Involving memory cells in new infections is biologically advantageous because they can respond faster and more effectively than naive T cells. Indeed, research in mice and humans has reinforced the theory of memory cross-reactivity. It was noted by the journal club moderator that not all infected individuals had an increase in virus-specific T cells. In instances where individuals had highly specific memory cells, they did not mount a defense with a large number of immune cells in response to the novel invader. By contrast, individuals with fewer memory cells mounted a larger response, likely to compensate for the lack of specificity.
- The field of immunology and T-cell activation is ever changing.
- Studying host response to both experienced and new pathogens allows insight into the way the body responds to and remembers foreign invaders. In the instance of COVID-19, researchers didn’t expect any memory cells to be involved in the immune response because the virus was completely new. However, some memory cells exhibited cross-reactivity and were able to begin protecting the host by targeting the virus early on.
Statistics for Immunologists
Understanding the Role of P Values in Scientific Research
By Sydnee Gould, LPD
Amid the influx of COVID-19-related studies flooding open-access journals, social media, and the news, it can be difficult to determine which results are statistically significant. Gauging statistical significance has been historically difficult due to frequent, unintentional misuse of P-values in journal publications. P-values help us make an informed decision to accept the null hypothesis or not. The null hypothesis is a theoretical concept in which the experimental group (or outcome) does not exist. In many instances, scientists use it as a measure of certainty or a confirmation that their experiment has worked. The reality is that P-values don’t measure likelihood or the possibility of the experimental hypothesis being “right” or “wrong.” In fact, P-values serve almost the opposite function because they assess the null hypothesis, not the experimental hypothesis.
Additionally, papers can confuse statistical significance with significant difference. That is, they determine that the difference between the control group and their sample is statistically significant but fail to determine if the difference is significant to the biological system or in a clinical setting. The paper’s advice was to utilize additional types of statistical tests to measure the validity or significance of the results. It’s also important to keep the perspective of your experiment in mind. If the experiment is meant to monitor an effect on humans, make sure it has both statistical and clinical insights.
- Approaching every research article with a critical eye is an essential skill as a scientist.
- COVID-19 has presented many opportunities to study various aspects of immunology, vaccinology, and virology under a new lens. However, don’t let the catchy headlines fool you, as many researchers—often by mistake—are misusing statistics to validate statistically or clinically insignificant findings.
- Moving forward, the field of science should place an emphasis on studying various statistical methods and how and when to best use them.
- Consult with a statistician before starting an experiment to ensure that the data will answer the question being asked. The NIH Library offers statistical support if needed.
Articles: Vaccination reshapes the virus-specific T cell repertoire in unexposed adult, The ASA Statement on p-Values: Context, Process, and Purpose, A guide to modern statistical analysis of immunological data
Infectious Disease & Vector Biology
Sand flies or needles: the importance of replicating natural conditions
By Michael Austin Stack, LCIM
Replicating natural conditions is not only difficult, but also critical to conducting proper research. It is difficult because needle inoculation is the easiest way to introduce a pathogen into mice, yet mice seldom encounter needles in the wild. It is critical because the route Leishmania, a sandfly-carried parasite, is administered into a mouse affects its ability to disseminate and cause disease.
The authors observed distinct cytokine responses for sandfly-bitten mice and needle-inoculated mice. The bacteria identified within the sandfly midgut drive an inflammatory response in which Leishmania spreads. The mice infected via needle, absent any bacteria native to the sandfly, efficiently cleared the parasite. This experiment demonstrates the importance of replicating natural conditions to reflect the real world.
- Bacteria in the sandfly midgut modulate the immune response.
- Leishmania can spread in mice bitten by sandfly but not in needle-inoculated mice.
- Seemingly unimportant details in a protocol can alter experimental outcomes.
Allergy & Immunology
Anaphylaxis is driven by a newly identified T cell population
By Michael Austin Stack, LCIM
You may have an allergy yourself, or you may know someone with an allergy. Many people with allergies carry EpiPens to prevent anaphylaxis, a life-threatening allergic reaction. But what makes some allergic reactions more severe than others? The authors of this paper sought the answer and characterized a new T-cell subset, the Tfh13 T cell. These T cells were found to expand in allergic models when exposed to allergens but not in healthy models with the same exposure. This subset was also found responsible for inducing an antibody response during anaphylactic shock; depleting Tfh13’s ability to produce the cytokine IL-13 stopped plasma-cell production of the high-affinity IgE. The beauty of this protocol is in its ability to not only identify the presence of these cells, but also the specific function that drives anaphylaxis.
- CD4+ T cells can drive specific antibody responses.
- A newly characterized T-cell population drives antibody production in anaphylaxis.
- This subset expands when challenged with a specific allergen, such as peanuts.
- Thorough research requires identifying the “who?” and the “how?”
Infectious Disease & COVID
Robust T cell response against SARS-CoV-2 persists up to 6 months
By Michael Austin Stack, LCIM
The discussion around protection against SARS-CoV-2 infection often leads to discussion about antibodies (humoral immunity), but the T-cell response (cellular immunity) is also critical to protection. T cells can kill cells directly or even drive antigen-specific antibody responses, as the previous article noted. This study highlights the T-cell response and its persistence after SARS-CoV-2 infection.
Shortly after infection, T-cell populations adapt to specifically target SARS-CoV-2 antigens. Many of these antigen-specific populations persist and mount a rapid, antigen-specific response at least 6 months later. This story will be important to follow as SARS-CoV-2 variants continue to emerge and challenge the immune system’s ability to mount effective recall responses.
- T cells produce a specific response to a specific antigen; some will survive and “remember” SARS-CoV-2 antigen.
- Memory T cells will rapidly respond to future encounters with antigen up to 6 months later.