The COVID-19 Textbook


CHAPTER 8 • Antibodies in COVID-19

As VOCs can systematically escape vaccine-induced nAbs, research efforts have shifted to focus on the development of pancoronavirus vaccines. 143,144 Significant progress has already emerged in the generation of pan-sarbecovirus vaccines, able to provide protection against all SARS-CoV-2 VOCs and SARS1. 144 Specifically, nanoparticle vaccines, using RBD domains from an array of variants, have already demonstrated striking progress toward the induction of broad responses able to limit VOC-mediated infections. 145,146 Novel designs focused on more conserved regions of the S pro tein, 147 or even other proteins, such as N proteins harboring many conserved T-cell epitopes, have also emerged, 148 aimed at leveraging both the T-cell and antibody response able to target current and potentially future VOCs while limiting disease. Both approaches are also being used to develop pan-betacoronavirus vaccines targeting sarbecoviruses and many common endemic coronaviruses that cause seasonal infections. 145,146 These strategies aim to significantly enhance the breadth of the immune response by targeting conserved elements and inducing broad antibody responses. PREVENTING TRANSMISSION Key to next-generation vaccines will be the development of strategies to drive immunity able to confer long-term protection against transmission. 142 Tissue-resident memory B and T cells form in response to mucosal infection 149 and help prevent reinfection, 150 with mucosal IgA known to be protective against coronaviruses. 151 High titers of S protein–specific IgA in the nasal passage are associated with milder COVID-19 in both children and adults. 152 Vaccine strategies aimed at driving sustained IgA responses at the virus’ portal of entry, the upper respiratory tract, could have a profound impact on preventing infection. However, most approved vaccines are administered intramuscularly and induce very limited tissue-resident antibodies. 153-156 Intranasal vaccination induces more robust and durable immune re sponses at the mucosal barrier, 157 potentially affording enhanced protection at the time of exposure. Intramuscular immunization with a mucosal boost has been shown to populate the mucosa with robust T and antibody responses. 158 Additionally, vectored vaccine administration to the mucosa has also shown robust nasal IgA responses. 159 Providing long-term protection via mucosal immunity may be challenging, as evidenced by some COVID-19 breakthrough cases occurring just weeks after an in fection, despite individuals being consistently exposed at the mucosal barrier. 160 Defining the precise immunologic mechanisms to drive broad and persistent nAbs in the upper respiratory tract is a key goal for next-generation vaccine development for SARS-CoV-2 and many other respiratory pathogens. OPTIMIZED BOOSTING Boosting is a common strategy to increase immunity, particularly in vulnerable populations such as im munocompromised individuals who require more doses to reach robust nAb titers or aging populations with partially anergized immunity. 137,138,161 mRNA vaccine–mediated boosting, for instance, reduces the risk of infection by 10- to 12-fold compared to the original (two-dose) vaccine in both the general population and in those more vulnerable to severe disease. 162 Cross-platform boosting may further increase effectiveness, by delivering the S antigen in the setting of different innate immune platform- specific stimuli that lead to higher quality T-cell activation and enhanced antibody breadth. 141 This is of particular concern in older populations, who have limited numbers of naive T cells, 163 where stronger responses using heterologous prime boosting strategies may be of particular advantage. Boosting with mRNA vaccines leads to higher levels of protection, 164 suggesting that specific platforms may induce superior activation of nAbs in older individuals. Further research is needed to define optimal boosting strategies to confer the highest level of immunity to vulnerable populations. MONOCLONAL ANTIBODIES AS THERAPEUTICS Early in the pandemic, convalescent plasma therapy (CPT) was trialed as a potentially high-impact, easily accessible therapeutic 165 from recovered patients. 166 Although several trials demonstrated lim ited benefit from CPT, 167-170 trials that used CPT early in the disease, in vulnerable populations,

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