Viruses are a major health problem for the general public and at risk populations.Normally, detection of antibody titers is the gold standard for determining theeffectiveness of the immune system following natural or vaccine caused immunization.However, determining the effectiveness of other parts of the immune system are lesscommon due to the difficulties with testing. Furthermore, there is a critical need toaddress other therapies in case vaccination is not successful in immuncompromisedpopulations. Exercise has been shown to increase the strength of the immune systemagainst many types of viruses and therefore could be simple way to improve immunityagainst the COVID-19 virus. The aim of this research is to determine the effects ofexercise on anti-viral immunity against many types of common viruses before and aftervaccination. We hypothesize that exercise will enhance the anti-viral immunity before andafter vaccination.Up to 30 healthy volunteers (age 18-44 years) will be recruited to participate in thisstudy. For completion of Aim 1, three visits are needed totaling around 7 hours of thepatient's time and for Aim 2, three visits are needed totaling around 4.5 hours of thepatient's time. The initial visit will be for pre-screening and if deemed healthy enoughto participate, an exercise test to determine the VO2 max of the participant will beconducted. The following visits will require a trained phlebotomist to insert anin-dwelling catheter and participants will undergo a 20-minute incremental exercisetrial. Approximately 50mL of blood will be collected at four different timepoints: atrest, 60% VO2 max, 80% VO2 max, and 1-hr post-exercise. All four collected blood sampleswill be used to expand viral specific T-cells and compare IFN-γ rele
Acute upper and lower respiratory tract infections (RTI) due to respiratory viruses, such
as, respiratory syncytial virus (RSV), influenza, parainfluenza virus (PIV) and human
metapneumovirus (hMPV) are a major public health problem. During the 2019-2020 influenza
season, the Center for Disease Control (CDC) determined that influenza accounted for 38
million illnesses, 18 million medical visits, 405,000 hospitalizations, and 22,00 deaths,
and annual costs of approximately 87.1 billion in disease management in the United
States. Simultaneously, the COVID 19 pandemic is currently a major health crisis across
of the United States and worldwide with the number of cases surpassing 50 million and
deaths totaling more than 1.3 million. Latent herpesviruses (cytomegalovirus (CMV),
Epstein Barr virus (EBV), and Varicella Zoster virus (VZV)) are other types of viral
infections that are easily controlled in healthy people but in immunocompromised people,
such as elderly or cancer patients, these latent viruses can become deadly. People
receiving allogenic hematopoietic cell transplantation (allo-HCT) are at high risk of CMV
infection and can lead to significant morbidity in transplant patients. Due to these
populations. An acute bout of exercise, as well as, chronic exercise training, have been
shown to enhance anti-viral immunity against many of these respiratory viruses and latent
herpesviruses. However, the immune response to viral infections is usually limited to the
detection of humoral responses and the ability to produce antibodies titers is the gold
standard for determining the effectiveness of the immune system in response to
vaccination. However, monitoring the cellular immune response following natural or
vaccine induced immunization less standardized. Numerous laboratory techniques have been
developed to test the cellular immune response including, phenotyping antigen specific
T-cells, intracellular staining of cytokines, ELISPOT or ELISA for antigen derived
cytokine production, and antigen specific cytotoxicity assays. However, theses assays are
laborious and typically require highly specialized lab equipment and techniques.
Interferon-gamma (IFN-γ) release assays have been developed to focus on cellular immunity
and could complement or replace these other laborious procedures. Thus we propose that a
single bout of exercise in humans will enhance the total antiviral immunity to numerous
respiratory viruses and latent herpesviruses, using a whole blood IFN-γ assay.
Secondly, there is a critical need to develop new therapeutics that can be used both
prophylactically and in the treatment of SARS CoV-2 infections. Adoptive cell therapy
with viral specific T-cells (VST) has been used effectively to treat viral infections in
immunocompromised patients, particularly in recipients of hematopoietic stem cell
transplantation. This procedure has been used for >25 years with evidence of safety and
efficacy. No group to our knowledge has attempted to manufacture SARS CoV-2 VSTs as a
potential therapeutic to prevent and/or treat refractory SARS Co-V-2 infections during
the current COVID-19 pandemic. Having a personalized or 'third-party' T-cell product that
is 'banked' and readily available could offer a life-saving intervention for many
'at-risk' individuals (e.g. the elderly, cancer patients, diabetics, transplant
recipients) should they develop COVID-19. Current COVID-19 vaccination strategies are
focused on inducing neutralizing antibodies. This strain-specific approach is limited
because immunity against drifted strains that emerge from one season to the next, or even
during a single season, is often lost. Given that T-cells offer protection against
multiple viral strains, there is strong rationale to develop a vaccine that targets
T-cells capable of providing coronavirus heterotypic immunity. Dendritic Cell (DC)
vaccines pulsed with viral antigen peptides have been used successfully to elicit immune
responses against influenza, hepatitis C and HIV and could, therefore, serve as a
personalized vaccine solution to the COVID-19 pandemic. In the present study, we plan to
demonstrate preclinical proof of concept for a DC based vaccine by attempting to immunize
"humanized" mice in vivo. Our proposed NOD-scid-IL2Rγnull (NSG) mouse model has been used
successfully to generate preclinical data for human DC and VST based vaccines.
Biological: COVID-19 Vaccine
COVID-19 Vaccine (mRNA or J&J)
Inclusion Criteria:
- 'low risk' for submaximal exercise testing in accordance with the risk
stratification guidelines published by the American Heart Association and the
American College of Sports Medicine (AHA/ACSM criteria). We will also determine the
participant's current vaccine status (influenza, chickenpox, etc) and COVID-19
infection status. Infection status will be determined via self-report and Spike
protein IgG titer levels We will simply ask the participant (self-report) when they
received the vaccine and, if they know, which vaccine they received (e.g. Moderna or
Pfizer for the COVID-19 vaccine). However, only participants that have been
vaccinated (1-3 weeks after second dose) or tested positive (greater than 2-months
symptom free) for COVID-19 by either PCR, antigen, or antibody testing will be
eligible for Aim 2. After providing informed consent, all participants will undergo
a comprehensive screening procedure to ensure that AHA/ACSM criteria are met.
Exclusion Criteria:
- Select a condition on the ACSM-AHA pre-exercise screening questionnaire indicating
that physician approval is required prior to exercise
- Current user of tobacco products or have quit within the previous 6-months
- Body mass index of >30 kg/m2, or waist girth of >102cm for men and >88cm for women
- Use over-the-counter medication known to affect the immune system (i.e. regular use
of ibuprofen/aspirin, anti-histamines or beta-blockers)
- chronic/debilitating arthritis
- Bedridden in the past three months
- Common illness (i.e. colds) within the past 6-weeks
- HIV, hepatitis, stroke, autoimmune disease, central or peripheral nervous disorders,
blood vessel disease, cardiovascular disease (CVD), or use of any prescription
medication
- Pregnant or breast-feeding; asthma, emphysema, bronchitis, kidney disease;
pheochromocytoma; diabetes; overactive thyroid; history of severe anaphylactic
reaction to an allergen; or are scheduled to have surgery.
- Individuals who pass the exclusion criteria detailed above but present with more
than one of the following CVD risk factors will also be excluded from the study:
family history of myocardial infarction, coronary revascularization, or sudden death
before 55 years of age in father or other male first-degree relative or before 65
years of age in mother or other female first-degree relative; hypertension (systolic
blood pressure of >140 mmHg or diastolic blood pressure >90 mmHg); dyslipidemia
(total serum cholesterol of >200 mg/dl); pre-diabetes (fasting blood glucose of
>100mg/dl but <126 mg/dl); high inflammation markers (hs-CRP>10 mg/L).
The University of Arizona
Tucson, Arizona, United States