key: cord-0771566-znar3u3k authors: Bhattacharya, Deepta title: Instructing durable humoral immunity for COVID-19 and other vaccinable diseases date: 2022-05-10 journal: Immunity DOI: 10.1016/j.immuni.2022.05.004 sha: ee9609bea5b1264d2bbedb4fd00fd08102e53344 doc_id: 771566 cord_uid: znar3u3k Many aspects of SARS-CoV-2 have fully conformed with the principles established by decades of viral immunology research, ultimately leading to the crowning achievement of highly effective COVID-19 vaccines. Nonetheless, the pandemic has also exposed areas where our fundamental knowledge is thinner. Some key unknowns are the duration of humoral immunity post-primary infection or vaccination, and for how long booster shots confer protection. As a corollary, if protection does not last as long as desired, what are some ways it can be improved? Here, I discuss lessons from other infections and vaccines that point to several key features that influence durable antibody production and the perseverance of immunity. These include 1) the specific innate sensors that are initially triggered; 2) the kinetics of antigen delivery and persistence; 3) the starting B cell receptor (BCR) avidity and antigen valency; 4) the memory B cell subsets that are recalled by boosters. I further highlight the fundamental B cell-intrinsic and -extrinsic pathways which, if understood better, would provide a rational framework for vaccines to reliably provide durable immunity. In January of 2020, metagenomic sequencing identified severe acute respiratory 38 syndrome coronavirus 2 (SARS-CoV-2) as the etiological agent of pneumonia outbreaks in 39 Wuhan (Wu et al., 2020; Zhou et al., 2020) . This local epidemic rapidly turned into a global 40 pandemic which, as of this writing, has led to over 400 million documented infections and 6 41 million deaths worldwide, both of which are almost certainly substantial underestimates of the 42 true toll. In large part due to substantial presymptomatic transmission ( hexosamine biosynthesis and antibody glycosylation, they can divert glucose into glycolysis and 208 use the resulting pyruvate for mitochondrial respiration when ATP stores are depleted (Lam et 209 al., 2016 ). Short-lived plasma cells are less able to engage this backup ATP metabolism 210 pathway. Long-lived plasma cells also express slightly higher surface levels of CD98, a common 211 subunit to several amino acid transporters, than do short-lived plasma cells, and their 212 mitochondrial respiration more resistant to amino acid reduction in vitro (Lam et 2017; Tooze, 2013)), these metabolic differences seem to be unlinked from proliferative status 220 (Lam et al., 2016 (Lam et al., , 2018 . Together, these findings suggest that metabolic pathways and the 221 ability to weather perturbations may be a defining characteristic of plasma cell longevity. That 222 these metabolic differences are seemingly unlinked from transcription is surprising on one hand. 223 Yet on the other hand, many metabolic pathways are established and maintained through 224 those elicited by symptomatic infections (Israel et al., 2021; . Relative to the 2 286 primary doses of the mRNA vaccines, the Ad26.CoV2.S vaccine induces lower initial levels of 287 antibodies (Munro et al., 2021) (Figure 1 ). Yet afterwards, these antibodies are maintained 288 relatively stably, perhaps even increasing with time (Sadoff et al., 2021b) . These data 289 demonstrate that early antibody response kinetics are not predictive of the duration of 290 production, and that there are currently no shortcuts to longitudinal studies. Thus, a key goal is 291 to define the molecular programs of plasma cell lifespan and the specific traits of vaccines and 292 infections that influence these programs. 293 As an aside, these types of comparisons have been used by some to argue that SARS-294 CoV-2 infections are a preferred way to generate immunity. This is a peculiar argument. The 295 purpose of these vaccines is to generate immunity without having to suffer the consequences of 296 COVID-19. Whether the resulting vaccine-induced immunity is subtly shorter-lived than that 297 caused by an infection seems beside the point. 298 299 The leading candidates of variables that influence durable immunity are 1) the specific 301 innate sensors that are triggered; 2) the kinetics of antigen delivery and persistence; 3) starting 302 antigen valency and B cell receptor avidity. There are several lines of evidence suggesting the 303 importance of the initial innate signals in imprinting the durability of immunity. Most clinically-304 used vaccines contain an adjuvant to induce transient inflammation. These can include 305 extrinsically added components, such as aluminum salts, or in the case of live-attenuated 306 presumably required for the formation of post-germinal center long-lived plasma cells (Hoft et 312 al., 2011) . This stands in contrast to live-attenuated influenza vaccines, which, at least in 313 children, induce strong T cell responses (Hoft et al., 2011) , and primary infections, which can 314 induce lifelong antibody production (Yu et al., 2008) . Studies in mice have also shown that the 315 nature of the adjuvant strongly influences the duration of antibody production. A cholera-toxin 316 based adjuvant induces much more stable antibody production than do alum or Ribi, an oil-in- week spacing between doses in the primary series, an increasing body of antibody and real-593 world effectiveness studies demonstrates that this is far from the optimal immunological timing. 594 increases effectiveness against variants of concern such as Delta and Omicron ( of what is immediately available now to what I expect will be coming in the next few years. First, 754 early evidence seems to suggest that the Ad26.Cov2.S vaccine, which yields modest antibody 755 levels as a single primary shot, may maintain antibody production more stably than another 756 mRNA dose when given as a booster (Liu et al., 2022) . Second, this 'best of both worlds' 757 strategy will be further supported once the Ad26. wins out remains to be seen, and may be driven as much by logistical and manufacturing 765 considerations as by effectiveness. Yet given all of the pre-clinical data thus far, it seems very 766 likely that such vaccines will at the minimum lengthen the amount of time it takes for the virus to 767 escape neutralizing antibodies. If one is allowed to hope a bit, combining these strategies could 768 leave one protected against SARS-CoV-2 for life. 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