Interestingly in their simulation model Lodding and colleagu

Interestingly, in their simulation model, Lodding and colleagues were able to predict their real rate of recipients with a high CMV viral load (1.4%, arbitrarily set at >18,200IU/mL) with the assumption of their lower doubling time of 4.3days. Using a shorter doubling time of 1.3days, the proportion of patient with a high viral load would have been 11%. The authors suggest that in cohorts with comparable doubling times, the screening interval can be safely extended. While this may decrease the cost burden due to less visits and screening costs, it should be emphasized that the most important goal is to reduce symptomatic CMV episodes in these vulnerable patients. We and others have shown that many factors including as strict adherence to a guideline with timely start of antiviral therapy in case of reactivation contribute to the success of the preemptive approach (). Of note, the number of patients with CMV disease was rather high and reached 31% during the observation time in the study by Lodding and colleagues.
A broadly effective HIV-1 Wnt-C59 would greatly contribute towards prevention of the 2.1 million new HIV-1 infections estimated to occur annually. Six HIV-1 vaccine efficacy trials in humans have thus far been conducted. Whereas most vaccines showed no efficacy in preventing from HIV-1 infection – and two actually increased infection rates in vaccine recipients – the RV144 Thai phase III HIV-1 vaccine trial is to date the only one to have shown efficacy, albeit marginally (31.2% decrease in HIV-1 acquisition at 42months post-vaccination) (reviewed in ()). Surely, this level of efficacy is insufficient; but these results gave hope that correlates of protection could be identified and improved upon as a path towards a more effective HIV-1 vaccine. In this issue, Nicely et al. present atomic-level details of the maturation pathway taken by a RV144 vaccine-induced antibody, CH58. The regimen administered to RV144 Thai trial volunteers consisted of four interspersed ALVAC™-HIV doses (canarypox-based viral vector with env/gag/pol components) boosted twice with AIDSVAX® B/E (bivalent monomeric gp120 protein) over six months (). Rigorous efforts to uncover correlates of protection in vaccine recipients revealed that IgG binding to a V1/V2 scaffold (HIV-1 gp120 variable loops 1 and 2 displayed on the murine leukemia virus gp70 protein) inversely correlated with infection. Two isolated antibodies from vaccine recipients, CH58 and CH59, bind to lysine 169 in gp120 V2 (), a position implicated by sieve analysis in blocking sequence-matched HIV-1 strains. Interestingly, these antibodies only neutralize HIV-1 weakly, but mediate effective antibody-dependent cell-mediated cytotoxicity (ADCC) as the mechanism to thwart HIV-1. Upon exposure to foreign antigens, precursor B cells undergo affinity-based selection and hypermutation of variable domains to gain in affinity and proliferate — a process termed affinity maturation. To shed light into the maturation pathway of the RV144 vaccine-induced CH58 antibody, Nicely and colleagues inferred its precursor sequence, and performed comparative structural and biophysical studies of the germline antibody and its mature counterpart. Only 11 mutations separate the precursor sequence from the mature antibody — a maturation pathway driven by the multivalent, prime-boost RV144 vaccine regimen. Conversely, the development of broadly neutralizing antibodies (bnAbs) in natural HIV-1 infection often requires more extensive affinity maturation. As an example, bnAb VRC01, which neutralizes ~90% of circulating HIV-1 isolates, has 66 residue alterations encoded in its variable light and heavy genes (). The CH58 affinity maturation pathway deepens our understanding of the level of somatic hypermutation achievable by current vaccination technology and serves as a benchmark to evaluate whether re-elicitation of extensively mutated bnAbs like VRC01 might ever be feasible by vaccination.