The objective of the study is to evaluate the safety, tolerability, and immunogenicity of 4 injections of VAX-31 (at 4 dose levels) compared to PCV20 in infants at 2, 4, 6, and 12-15 months of age, in addition to receiving routine US concomitant vaccines. Stage 1 of the study will comprise 3 dose ascending cohorts. Stage 2 of the study will enroll approximately 352 subjects. Stage 3 of the study will enroll approximately 500 subjects.

Inclusion Criteria:

1. Healthy male or female infant ≥42 days to ≤89 days.
2. Full-term infant at least 37 weeks gestational age at birth.
3. Afebrile for ≥72 hours with an tympanic or rectal temperature <38.0°C (<100.4°F) before receipt of study vaccine.*Criterion applies to each vaccination. If not met, visit may be rescheduled for a time when no longer febrile for ≥72 hours.
4. Able to attend all scheduled visits and comply with the study procedures.
5. Subject's parent/legal guardian is able to read and understands the study procedures, alternate treatments, risks and benefits, and provides written informed consent.
6. Subject's parent/legal guardian is able to fill out an eDiary of solicited AE and take daily tympanic temperature and measurements of local injection site reactions for the 7 days after each study vaccination.
7. Subject's parent/legal guardian has an email address and access to a computer or smartphone with internet to complete the eDiary.

Exclusion Criteria:

1. History of invasive pneumococcal disease (positive blood culture, positive cerebrospinal fluid culture, or other sterile site) or known history of other culture positive pneumococcal disease.
2. Previous receipt of a licensed or investigational vaccine (excluding 1 dose of hepatitis B vaccine).
3. Known hypersensitivity to any vaccine.
4. Known or suspected impairment of immunological function (e.g., asplenia, human immunodeficiency virus, primary immunodeficiency).
5. Use of any immunosuppressive therapy or planned use through the last blood draw (Visit 6). Receipt of a <14-day course of systemic corticosteroids is not exclusionary if completed ≥1 month prior to first study vaccination. Topical and inhaled/nebulized steroids are also permitted.
6. History of failure to thrive or prior hospitalization for any chronic condition.
7. Subject has a bleeding disorder contraindicating IM vaccination.
8. Subject or his/her mother has documented hepatitis B surface antigen-positive test.
9. Subject has a known neurologic or cognitive behavioral disorder.
10. Subject has a known clinically significant congenital malformation or serious chronic disorder.
11. Receipt of a blood transfusion or blood products, including immunoglobulins.
12. Receipt of any investigational study product since birth, currently participating in another interventional investigational study, or plans to receive another investigational product while on study.
13. Any infant who cannot be adequately followed for safety according to the protocol plan.
14. Any other reason that in the opinion of the Investigator may interfere with the evaluation required by the study.

Vaxcyte is committed to providing access to anonymized data from the company's clinical trials for the purpose of legitimate scientific research. Requests for data may be addressed to datasharing@vaxcyte.com. Requests must be accompanied by a detailed analysis plan and will be reviewed for scientific validity. Data will be made available after initial product approval. Sharing of data may require execution of a data-sharing agreement.

Individual participant data will be shared after deidentification and made available starting 6 months after initial product approval.

Criteria will depend on the specific proposal received and may include qualification of the scientific researchers, potential contribution to the research field, scientific rigor of statistical and analytical methods, and other criteria appropriate for the proposal.