# Lessons Learnt from COVID-19: Computational Strategies for Facing Present and Future Pandemics
## 1 The COVID-19 Pandemic
### Viral Variants  
Due to its exposition on the external surface of the SARS-CoV-2 membrane and its pivotal role in the virus's ability to infect host cells, the spike protein is often subjected to mutations that alter the virus's infectivity and antigenicity [93; 94]. Therefore, since the spreading of the original viral strain (Wuhan-Hu-1) began, several viral variants appeared on the scene [95], particularly in third-world nations where collective sanitary practices such as social and physical distancing [96] or wearing face masks in public places [18] were hardly implementable [97].  
The insurgence of novel viral strains with different susceptibility to the protective effect of vaccines [98] demands periodical updates of their original formulations coupled with multiple booster shots to maintain their efficacy [99], thus hampering the management of the pandemic based on massive vaccination of the world population [100; 101].  
Among the large pool of SARS-CoV-2 mutations [102], some gathered the scientific community's attention due to their increased fitness, gaining the \"variant of concern\" (VOC) status [103].  
The first ever SARS-CoV-2 VOC was the B.1.1.7 variant, more commonly referred to as the \"Alpha\" or \"English\" variant due to being first identified in November 2020 in the Kent region of the United Kingdom [104; 105]. Despite worries about the higher transmissibility compared to other circulating variants at the time [106; 107], clinical studies demonstrated how mAbs, CP, and especially vaccines, were still able to confer protection against B.1.1.7 [108; 109; 110], containing its impact on the sanitary system [111].  
Unfortunately, soon after the emergence of the Alpha variant, a more threatening VOC arose. The B.1.617.2 variant, commonly known as the \"Delta\" or \"Indian\" variant, due to being first identified in India in late 2020, quickly overthrow B.1.1.7 thanks to its strikingly increased transmissibility [105]. The advent of the Delta variant was associated with the first signs of reduced protection provided by mAbs, CP, and most importantly, vaccines [112; 113; 114], thanks to its increased immune system evasion capability [115], posing a heavier workload on the sanitary system [116].  
The latest hallmark in the history of SARS-CoV-2 variants is represented by the B.1.1.529 variant, first detected in South Africa and more often called the Omicron variant [117]. The combination of increased transmissibility [118] and immune system evasion [119] conferred this variant a net selective advantage in bypassing the protection provided by the complete primary vaccination cycle and a variety of clinically utilized mAbs [120; 121; 122] compared to other circulating strains. The ground-breaking impact the Omicron variant had on the worldwide spread of SARS-CoV-2 even led to the introduction of the \"booster dose\" to compensate for the reduced coverage of the primary vaccine cycle [98; 123].  
Lately, several subvariants germinated from the original Omicron strain (also labeled as BA.1), namely BA.2, BA.3, BA.4, and BA.5 [124; 125; 126]. Although different studies indicated how the first identified Omicron subvariants (BA.2 and BA.3) were similarly susceptible to existing treatments despite their increased transmissibility [127; 128; 129], it also emerged how the most recently identified ones (BA.4 and BA.5) are significantly more efficient in evading the immune response [130; 131; 132].  
These findings indicate that SARS-CoV-2 continued to evolve by increasing its immune-evasion capability rather than counting on sheer higher transmissibility, sustaining the virus spread even in populations with high vaccination frequency and recovery rates [130; 131; 132].