Universal Immunization to Fortify Immunotherapy Efficacy and Response

Inclusion Criteria:

* Adults ≥ 18 years of age.
* Histologically or cytologically confirmed stage IV non-small cell lung cancer (NSCLC), defined as: adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and NSCLC not otherwise specified; with clinical disposition to front-line therapy, with pembrolizumab and chemotherapy
* ECOG Performance Status of 0 to 2.
* Willing to receive Pfizer-BioNTech mRNA COVID-19 vaccine (for vaccine arms).
* Written informed consent obtained from the subject and the subject agrees to comply with all the study-related procedures.
* Subjects must not have more than one active malignancy at the time of enrollment (Subjects with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen or primary endpoint \[as determined by the treating physician or approved by the PI\] are eligible for this trial).
* Women of childbearing potential (WOCBP) will be given a pregnancy test (blood or urine) prior to the start of treatment and must be using an adequate method of contraception to avoid pregnancy throughout the study and for at least 5 months after the last dose of study treatment to minimize the risk of pregnancy. Prior to study enrollment, subjects of childbearing potential must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy.

Adequate contraception methods for WOCBP include:

* Barrier methods

  * Male and female condoms
  * Vaginal diaphragm
  * Cervical cap
  * Vaginal sponge
* Hormonal medication and devices

  * Birth control implant (i.e. Nexplanon)
  * Intrauterine device (IUD, made of copper or progestin)
  * Hormonal contraception
  * Birth control pills (combined (estrogen and progestogen containing))
  * Contraceptive vaginal ring (i.e. NuvaRing)
  * Patch (i.e. Xulane)
  * Progestin only pill (mini pill)
  * Depo-Provera (birth control shot or Depo)
* Abstinence
* Vasectomized male partner

WOCBP includes any subject who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or who is not post-menopausal. Post-menopause is defined as:

* Amenorrhea that has lasted for ≥ 12 consecutive months without another cause, or
* For subjects with irregular menstrual periods who are taking hormone replacement therapy (HRT), a documented serum follicle-stimulating hormone (FSH) level of greater than 35 mIU/mL.

  * Subjects with partners of child-bearing potential must agree to use physician-approved contraceptive methods (e.g., abstinence, condoms, vasectomy) throughout the study and should avoid conceiving children for 5 months following the last dose of study treatment.

Exclusion Criteria:

* Dispositioned to targeted therapy (e.g., EGFR, ALK, ROS1).
* Determination by the treating physician that treatment with pembrolizumab with chemotherapy is not an appropriate intervention for the participant.
* Known hypersensitivity or allergy to any component of the mRNA COVID-19 vaccines (Pfizer-BioNTech or Moderna), including polyethylene glycol (PEG) or polysorbate
* Administration of a vaccine containing live virus within 30 days prior to the first dose of trial treatment. Note: Most flu vaccines are killed viruses, with the exception of the intra-nasal vainer (Flu-Mist) which is an attenuated live virus and therefore prohibited for 30 days prior to first dose.
* Receipt of any other COVID-19 vaccine or investigational vaccine within 60 days prior to enrollment.
* Uncontrolled or unstable comorbid conditions (e.g., active infection, unstable cardiovascular disease, history of vaccine-related myocarditis, or uncontrolled autoimmune disease) that, in the opinion of the investigator, could interfere with study participation or pose additional risk.
* History of any other disease, metabolic dysfunction, clinical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of protocol therapy or that might affect the interpretation of the results of the study or that puts the subject at high risk for treatment complications, in the opinion of the treating physician.
* Subjects who are confirmed to be pregnant or breastfeeding.
* Prisoners or subjects who are involuntarily incarcerated, or subjects who are compulsorily detained for treatment of either a psychiatric or physical illness.