Background: COVID-19 remains a rapidly evolving and deadly pandemic worldwide. This necessitates the continuous assessment of existing diagnostic tools for robust, up-to-date and cost-effective pandemic response strategy. We sought to determine the infection rate (PCR-positivity) and degree of spread (IgM/IgG) of SARS-CoV-2 in three university settings in Cameroon Method: Study volunteers were recruited from November 2020 to July 2021 among COVID-19 non-vaccinated students in three Universities from two regions of Cameroon (West and Centre). Molecular testing was performed by RT-qPCR on nasopharyngeal swabs and IgM/IgG antibodies in plasma were detected using the Abbott Panbio IgM/IgG rapid diagnostic test (RDT) at the Virology Laboratory of CREMER/IMPM/MINRESI. The molecular and serological profiles were compared and, p<0.05 considered statistically significant. Results: Amongst the 291 participants enrolled (mean age 22.59±10.43 years), 19.59% (57/291) were symptomatic and 80.41 %(234/2691) asymptomatic. Overall COVID-19 PCR-positivity rate was 21.31% (62/291), distributed as follows: 25.25% from UdM-Bangangte; 27.27% from ISSBA-Yaounde and 5% from IUEs/INSAM-Yaounde. Women were more affected than men (28.76% [44/153] vs. 13.04% [18/138], p<0.0007) and they significantly expressed more IgM+/IgG+ (15.69% [24/153] vs. 7.25% [10/138], p<0.01). Participants from Bangangté, the nomadic, and the “non-contact cases” mainly presented an active infection compared to those from Yaoundé (p= 0.05; p=0.05 and p=0.01 respectively). Overall IgG seropositivity (IgM-/IgG+ and IgM+/IgG+) was 24.4% (71/291). A proportion of 26.92% (7/26) presenting COVID-19 IgM+/IgG- had negative PCR versus 73.08% (19/26) with positive PCR, p<0.0001. Furthermore, 17.65% (6/34) with COVID-19 IgM+/IgG+ had negative PCR as compared to 82.35% positive PCR (28/34), p<0.0001. Lastly, 7.22% (14/194) with IgM-/IgG- had a positive PCR. Conclusion: This study calls for a rapid preparedness and response strategy in higher institutes in case of any future pathogen with pandemic or epidemic potentials. The observed disparity between IgG/IgM and viral profile supports prioritizing assays targeting the virus (nucleic acid or antigen) for diagnosis and antibody screening for sero-surveys