Alpha, Beta, Delta, Omicron, and SARS-CoV-2 Breakthrough Cases: Defining Immunological Mechanisms for Vaccine Waning and Vaccine-Variant Mismatch

Abstract

The COVID-19 pandemic, caused by the SARS-CoV-2 coronavirus, is responsible for over 400 million cases and over 5. 5 million deaths worldwide. In response to widespread SARS-CoV-2 infection, immunization of the global population has approached 60% one dose and 54% full dose vaccination status. Emerging data indicates decreasing circulating antibody levels as well as decreases in other immune correlates in vaccinated individuals. Complicating the determination of vaccine effectiveness is the concomitant emergence of novel SARS-CoV-2 variants with substantial antigenic differences from the ancestral D614G strain. The Omicron variant (B.1.1.529) spike protein has over 30 mutations compared with the D614G spike protein, which was used to design most SARS-CoV-2 vaccines in use today. Therefore, breakthrough cases of SARS-CoV-2 infections or severe disease in fully vaccinated individuals must be interpreted with caution taking into consideration vaccine waning and the degree of vaccine variant-mismatch resulting in adaptive immune evasion by novel emerging SARS-CoV-2 variants.

Physical-Chemical Regulation of Membrane Receptors Dynamics in Viral Invasion and Immune Defense

“…These mechanical regulations during viral invasion were further validated by the more infectious D614G mutation of SARS2-S. D614G mutation, located outside of the RBD of the S1 subunit, causes more fatality and is inherited in Alpha, Beta, Delta and recent Omincron SARS-CoV-2 virus 82 , 83 , 84 , 85 , 86 , 87 , 88 . A recent study showed that D614G converts the S1 protein conformation (RBD and N-terminal domains of S1 subunit) to an ACE2-binding fusion-competent state and thus may increase viral infectivity [89] .…”

Considerations regarding Interpretation of Positive SARS-CoV-2 Molecular Results with Late Cycle Threshold Values

“…A study of breakthrough infections caused by the Delta variant of SARS-CoV-2 showed similar peak viral loads between vaccinated and unvaccinated subjects ( 40 ). Specimens collected from vaccinated individuals with breakthrough infections can have late CT values, with both Delta and Omicron variants ( 41 – 43 ).…”

Molecular mechanisms responsible for SARS-CoV-2 antibody waning and vaccine escape in Omicron sublineages BA.4 and BA.5

“…Potential solutions to vaccine waning include (but are not limited to): i) further investigation into second generation, multivalent vaccines, ii) the humoral IgA mucosal response, and iii) development beyond S-targeting vaccines towards broad stimulation and priming of adaptive T-and B-cell mediated memory responses. A multivalent COVID-19 vaccine may address deficiencies in existing mRNA-based vaccines, such as the existing reliance on multiple doses and the lack of infection [1]. Multivalent vaccines rely on incorporating SARS-CoV-2 S epitopes from multiple variants, rather than just a single variant.…”

“…For COVID-19, this is neutralizing antibodies at mucosal sites in the nose, throat, and upper respiratory tract achieved by intranasal (IN) vaccines [13]. Early data indicate that a heterologous vaccination with an mRNA intramuscular (IM) vaccine prime coupled with an IN boost could result in broader protection, both systemically and at the infection site [1,14].…”

“…A common theme of the COVID-19 pandemic is the increasing incidence of "breakthrough infections". A breakthrough infection is defined as a fully vaccinated individual (that is, already having two or more doses of a reputable SARS-CoV-2 vaccine) contracting a SARS-CoV-2 infection [1]. Although messenger RNA (mRNA)-based vaccines offer vaccinees protection from severe disease, it currently remains to be elucidated whether long-term protection and recurrent vaccine doses are necessary for sustained protection from infection.…”