SARS-CoV-2 transmission and disease with varying severity occur through a complex interplay of public health and social measures (non-pharmaceutical interventions), behavior, social background, past infection, and vaccination. The emergence of new variants and the potential waning of vaccine-induced immunity further complicated the situation. Teasing apart and analyzing the association between these factors was vital for informing policies and risk communication. This PhD aimed to (1) elucidate social and behavioral risk factors associated with SARS-CoV-2 infection and (2) evaluate COVID-19 vaccine effectiveness (VE) for both symptomatic infection and severe disease in Japan and the Philippines. These were mainly done by setting up and conducting multi-center case-control studies in healthcare facilities in both countries. Multiple socio-behavioral factors were associated with SARS-CoV-2 infection, including social gatherings and school/work, many of which were in line with the policy/risk communication implemented. Some of these factors, together with anxiety, were monitored over time, together with the number of reported cases in Japan. A triangulation approach using community controls (in addition to test-positive and test-negative individuals) with an online survey to assess the behavioral risk factors was explored and showed the potential usefulness of using such control groups. The prospective approach enabled exploration of the influence of preventive measures such as mask-wearing and high-risk behaviors on estimates of COVID-19 VE against symptomatic infection. This was an important consideration for COVID-19, where differential exposures may exist between vaccinated and unvaccinated individuals due to, for example, vaccine passports. In Japan, COVID-19 VE against symptomatic infection was continuously monitored through the Alpha-dominant period, Delta-dominant period, Omicron-dominant period (including BA.1/BA.2 and BA.5 to differentiate immune escape and waning immunity), and also for Omicron-containing bivalent vaccines. Also, the association between SARS-CoV-2 infection and influenza vaccination status was assessed as a negative control exposure (during the period with extremely low influenza activity) with no association found. In the Philippines, ethics and alignment with internal stakeholders proved challenging and the study was initiated after the first Omicron peak. Biases due to complex immune histories made it challenging to assess VE against symptomatic infection, but the results did suggest a possible moderate effect of boosters. Further, in Japan, online survey data on the general population was utilized to identify socio-behavioral factors associated with the lack of intention to receive COVID-19 vaccines and to inform vaccination policy further. Next, emerging evidence suggested that VE wanes against mild symptomatic infection and is also less effective in the setting of Omicron. This resulted in the target product profile shifting to severe disease with an increasing need to evaluate VE against severe disease. Therefore, VE against severe COVID-19 was also evaluated in hospitals that admit severe COVID-19 cases in each country. In doing so, data on various severity levels (hospitalization, oxygen use, invasive mechanical ventilation use, and death) and on whether oxygen use was due to COVID-19 or other diseases among those who tested positive for SARS-CoV-2 were collected. This was because incidental infection found during hospital admission screening was an issue in using a database to conduct VE studies due to lower VE against infection than against severe diseases with past studies showing a wide range of VE estimates against hospitalization. VE of 2 doses of COVID-19 was high in the pre-Omicron period and moderate to high against Omicron for multiple severe outcomes in both countries. Among categories with sufficient sample sizes, there was a consistent trend towards higher VE for more severe and specific outcomes. These results demonstrate the usefulness of severe and specific outcomes to accurately measure VE, as recommended in World Health Organization (WHO) guidance in the setting of intense transmission as seen during Omicron. Additionally, in collaboration with the WHO Western Pacific Regional Office, a practical protocol to implement COVID-19 VE studies was also developed for use in other countries. Finally, to inform future health emergencies, epidemics, and potential pandemics, the challenges and lessons learned from setting up and executing operational research to evaluate public health interventions, including non-pharmaceutical interventions and vaccines, were summarized.