Inclusion Criteria:
1. Provide written informed consent prior to initiation of any study procedure.
2. Are able to understand and comply with planned study procedures and be available for all study visits.
3. Are males or non-pregnant, non-breastfeeding females, 18 to 49 years of age, inclusive at time of screening and enrollment.
4. Must agree to collection of venous blood and nasal absorption specimens per protocol and enrollment in DMID Protocol No. 19-0025 biorepository protocol for secondary research and use of residual biologic specimens.
5. Are in good health\* and do not have clinically significant medical, psychiatric, chronic or intermittent health conditions including those listed in Exclusion Criteria (Section 1).
\*As determined by medical history, medication use, and physical examination to evaluate ongoing chronic medical or psychiatric diagnoses or conditions, defined as those that have been present for at least 90 days, which would not affect the assessment of the safety of subjects or the immunogenicity of study vaccinations. These medical diagnoses or conditions should be stable for the last 60 days (no hospitalizations, emergency room \[ER\] or urgent care for condition \[excluding musculoskeletal conditions\], or invasive medical procedure and no adverse symptoms that need medical intervention such as medication change/supplemental oxygen). This includes no change in chronic prescription medication, dose or in the 60 days prior to enrollment. Any prescription change that is due to change of health care provider, insurance company, etc., or that is done for financial reasons, as long as in the same class of medication, will not be considered a deviation of this inclusion criterion. Subjects may be on chronic or as needed (prn) medications if, in the opinion of the site PI or appropriate sub-investigator, they pose no additional risk to subject safety or assessment of reactogenicity and immunogenicity and do not indicate a worsening or treatment of continued symptoms of medical diagnosis or condition. Note: Low dose topical, corticosteroids as outlined in the Subject Exclusion Criteria (see Section 1) as well as herbals, vitamins and supplements are permitted.
6. Does not have an ongoing symptomatic condition\* for which subject has had or has ongoing medical investigations but has not yet received a diagnosis or treatment plan.
\*e.g., ongoing fatigue without a diagnosis for symptom.
7. Pulse is 50 to 100 beats per minute, inclusive.
8. Systolic blood pressure is 90 to 140 mmHg, inclusive.
9. Diastolic blood pressure is 55 to 90 mmHg, inclusive.
10. Body mass index (BMI) of 18 kilograms/square meter (kg/m\^2) (inclusive) to \<35 kg/m\^2 at screening
11. Women of childbearing potential\* must agree to use or have practiced true abstinence\*\* or use at least 1 acceptable primary form of contraception.\*\*\*
\*Not of child bearing potential - post-menopausal females (defined as having a history of amenorrhea for at least one year) or a documented status as being surgically sterile (hysterectomy, bilateral oophorectomy, salpingectomy, or Essure placement with history of documented radiological confirmation test at least 90 days after the procedure).
\*\*True abstinence is 100% of time no sexual intercourse (male's penis enters the female's vagina). (Periodic abstinence \[e.g. calendar, ovulation, symptothermal, post-ovulation methods\] and withdrawal are not acceptable methods of contraception).
* Acceptable forms of primary contraception include monogamous relationship with a vasectomized partner who has been vasectomized for 180 days or more prior to the subject receiving the study product, tubal ligation, intrauterine devices, birth control pills, and injectable/implantable/insertable hormonal birth control products.
* Must use at least one acceptable primary form of contraception or true abstinence for at least 30 days prior to receipt of study product and at least one acceptable primary form of contraception or true abstinence for at least 30 days following receipt of study product.
12. Women of childbearing potential must have a negative serum HCG pregnancy test at screening and a negative urine HCG pregnancy test within 24 hours prior to the study vaccination.
13. Male participants receiving VRC H1ssF\_3928 mRNA-LNP must agree to refrain from donating sperm and to use contraception until Day 60 after vaccination.\*
* Acceptable contraception includes abstinence from intercourse with a female of childbearing potential or use of a male condom when engaging in any activity that allows for passage of ejaculate to a female during the intervention period for at least 60 days after study vaccination.
* Males in the immunogenicity comparator group do not have to refrain from sperm donation or abstain from intercourse or agree to use a male condom for purposes of this study.
14. Must have received at least one licensed seasonal influenza vaccine within the previous 5 seasons.
Exclusion Criteria:
1. Have an acute illness\* or fever (body temperature \> / = 38.0 degrees Celsius/100.4 degrees Fahrenheit), as determined by the site Principal Investigator (PI) or appropriate sub-investigator, within 72 hours prior to study vaccination.
\*An acute illness which is nearly resolved with only minor residual symptoms remaining is allowable if, in the opinion of the site PI or appropriate sub-investigator, the residual symptoms will not interfere with the ability to assess safety parameters as required by the protocol.
2. Have any medical disease or condition that, in the opinion of the site PI or appropriate sub-investigator, is a contraindication to study participation.\*
\* Including acute, subacute, intermittent or chronic medical disease or condition that would place the subject at an unacceptable risk of injury, render the subject unable to meet the requirements of the protocol, or may interfere with the evaluation of responses or the subject's successful completion of this trial.
3. Has a screening laboratory\* \> Grade 1.
\*White blood cell count, absolute neutrophil count, absolute lymphocyte count, hemoglobin, platelet count, prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen, creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total bilirubin, lipase.
4. Has a positive urine toxicology screen (i.e., non-prescribed amphetamines, cocaine, and opiates).
5. Electrocardiogram (ECG) is deemed to be clinically significant by the PI or appropriate sub-investigator.
6. Total iron binding capacity, iron, ferritin and troponin (hsTnl) outside the laboratory normal range at screening.
7. Have any known or suspected immunosuppressive condition, acquired or congenital, or autoimmune conditions as determined by history and/or physical examination.
8. Have immunosuppression as result of treatment including a recent history (within 6 months prior to administration of study vaccine) or use of immunosuppressive or other immune-modifying drugs.
9. Use of anticancer chemotherapy or radiation therapy (cytotoxic) within 3 years prior to study vaccination.
10. Have known active or recently active (12 months) neoplastic disease or a history of any hematologic malignancy. Non-melanoma, treated, skin cancers are permitted.
11. Have known human immunodeficiency virus (HIV), hepatitis B or hepatitis C infection at screening.
12. Have a positive test result for hepatitis B surface antigen, hepatitis C virus antibody, or HIV types 1 or 2 antibodies at screening.
13. Have known chronic liver disease, including fatty liver disease.
14. Have a known allergy or severe allergic reaction to any components of the study vaccine (including polyethylene glycol \[PEG\]) or the seasonal influenza vaccine (including egg protein).
15. Have a history of a severe reaction following previous immunization with an investigational, authorized, or approved influenza vaccine or mRNA or LNP-containing vaccine containing vaccine.
16. Have a history of Guillain-Barré Syndrome.
17. Have a known history of myocarditis or pericarditis.
18. Have a history of alcohol or drug abuse within 3 years prior to study vaccination.
19. Have any diagnosis, current or past, of schizophrenia, bipolar disease or other psychiatric diagnosis that may interfere\* with subject compliance or safety evaluations.
\*As determined by the site PI or appropriate sub-investigator.
20. Have been hospitalized for psychiatric illness, history of suicide attempt, or confinement for danger to self or others within 5 years prior to study vaccination.
21. Have taken oral or parenteral (including intra-articular) corticosteroids of any dose within 30 days prior to study vaccination. Intranasal or topical (skin or eyes) corticosteroids are permitted.
22. Have taken high-dose inhaled or nebulized corticosteroids\* within 30 days prior to study vaccination.
\*High-dose defined as per age as using inhaled high-dose per reference chart in the National Heart, Lung and Blood Institute Guidelines for the Diagnosis and Management of Asthma (EPR-3) or other lists published in UPTODATE
23. Have any significant disorder of coagulation requiring ongoing or intermittent treatment.
24. Have received seasonal influenza vaccine within 90 days prior to enrollment or plans to receive a seasonal influenza vaccine 60 days after study vaccination.
25. Have received any approved or authorized vaccines other than seasonal influenza vaccine within 60 days before enrollment or plans to receive an approved or authorized vaccine 60 days after study vaccination.
26. Have a known history of documented influenza infection within the past 90 days.
27. Have a history of receipt of an investigational H1 influenza vaccine within the past 10 years.
28. Have a history of receipt of a ferritin-based vaccine or an investigational H5 influenza vaccine.
29. Previous participation in DMID Protocol No. 18-0010 human influenza challenge study.
30. Received immunoglobulin and/or any blood products (except Rho D immunoglobulin) within the 90 days prior to study vaccination.
31. Received an experimental agent \*within 60 days prior to the study vaccination or expect to receive another experimental agent during the trial-reporting period.\*\*
\*Including vaccine, drug, biologic, device, blood product, or medication.
\*\*Other than from participation in this trial
32. Are participating or plan to participate in another clinical trial with an interventional agent\* that will be received during the trial-reporting period.\*
* Including licensed or unlicensed vaccine, drug, biologic, device, blood product, or medication.
* Approximately 12 months after the first study vaccination.
33. The subject has any abnormality or permanent body art (e.g., tattoo) that, in the opinion of the investigator or appropriate sub-investigator, would obstruct the ability to observe local reactions at the injection site.
34. Donation of blood or blood products within 30 days prior to dosing and plans to donate within 60 days following dosing.
35. Has had significant exposure to someone with laboratory-confirmed severe acute respiratory syndrome (SARS-CoV-2) infection or influenza in the 14 days prior to screening or during the period between screening and enrollment visit.\*
\*Defined by the Centers for Disease Control and Prevention (CDC) as a close contact with someone who has COVID-19.
36. Has had a positive SARS-CoV-2 test (home or laboratory-based) within 14 days prior to the screening visit or during the period between screening and enrollment visits.
