Annals of Internal Medicine | 2021
Will We Have the Tools to Address a Reemergent Zika Virus Epidemic?
Abstract
Zika virus (ZIKV) is a flavivirus transmitted by the bite of an Aedes genus mosquito, as well as from motherto-fetus, during sexual intercourse, and through blood transfusions. Most commonly, infection is asymptomatic or mildly symptomatic. However, infection during pregnancy is associated with adverse fetal outcomes, including stillbirth, and birth defects, such as microcephaly and other brain anomalies, ocular abnormalities, congenital contractures, and increased muscle tone (1). Congenital ZIKV syndrome (CZS) presents a heavy burden to families and society. Moreover, other severe outcomes after ZIKV infection have been noted, including Guillain–Barr e syndrome, encephalitis, and neurodevelopmental consequences for children infected postnatally (2, 3). Two articles in Annals focus on strategies to reduce ZIKV transmission through immunization (4) and screening of the blood supply (5). Russell (5) reports a simulation study that estimates the rates of ZIKV transmission through blood transfusion and the cost-effectiveness of current blood supply screening practices in the United States. During the 2015 to 2016 ZIKV epidemic, the U.S. Food andDrug Administration and its Blood Products Advisory Committee (BPAC) mandated universal screening, then in 2018 permitted minipool testing. Minipool testing typically involves performing nucleic acid testing on a pool of 6 or 16 donations, releasing the blood from negative pools, and individually testing each donation from positive pools before release. On the basis of the simulations and frequency of ZIKV-positive blood donations detected in 2018, Russell concluded that transfusion-associated ZIKV infection causing mild febrile illness, CZS, and Guillain–Barr e syndrome would occur once every 1.3 years, 1484 years, and 1035 years, respectively. Minipool testing was estimated to cost $5.1 billion per quality-adjusted life-year gained compared with no screening. The BPAC should consider these findings along with other data when discussing the next recommendations for ZIKV screening of the blood supply. If BPAC adopts a “no-screening” approach, it will be important to establish clear guidance regarding ZIKV surveillance and the threshold rates of infection that should trigger resumption and type of blood supply screening. Note that the spectrum of potential complications from ZIKV infection is broader than that considered in Russell s model, which focused on CZS. Further, the study did not consider secondary sexual transmission after transfusion-associated ZIKV infection, whichmay lead to additional cases. Immunization against infectious diseases is one of medicine s greatest accomplishments. Salisch and colleagues (4) report a phase 1 study of a candidate vaccine to prevent ZIKV infection. Although other clinical trials of ZIKV vaccines have been published (6), this is the first randomized, double-blind, placebo-controlled trial in healthy adults of a viral-vectored vaccine with a replicationincompetent adenoviral (Ad) vector encoding the ZIKV M and Env proteins (Ad26.ZIKV.001). The 100 participants in this U.S.–based study were 55% female and 72% White. Two doses of Ad26.ZIKV.001 were safe, caused mild to moderate reactogenicity, and induced persistent neutralizing antibody responses. Crucially, antibody responses up to 1 year after vaccination were observed in at least 80% of participants in both 2-dose (high and low) groups, indicating that a low dose would be sufficient. A single high-dose vaccine achieved a similar level of neutralizing antibody titers at 1 year but had lower peak neutralizing responses than the 2-dose strategies, and thus may be suboptimal in an outbreak scenario. Of interest, 7 participants (7%) had preexisting antibodies to the viral vector and 5 of the 7 were assigned to the 2-dose vaccine groups, but reactogenicity and immunogenicity results were not stratified on the basis of this factor. Because the Ad26 viral–vectored vaccine design is also being developed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (7), this preexisting immunity may be expected to increase in regions where this vaccine is adopted andmight influence the efficacy of this vaccine construct. Preexisting antivector immunity and immune cell activation upon immunization have been proposed as mechanisms of enhanced HIV-1 acquisition in a clinical trial using an Ad5 vaccine vector, and therefore should be examined closely in studies of Ad-vectored vaccines (8). A major hurdle in ZIKV vaccine development is the inability to conduct large efficacy studies in the absence of a current outbreak. Salisch and colleagues provide some animal model efficacy data demonstrating that purified IgG from trial participants at day 85 after immunization protectedmice from ZIKV infection. Although helpful given the existing epidemiologic constraints, these data are obviously not conclusive for human protection. A further challenge for ZIKV vaccine efficacy trials will be to demonstrate fetal protection from CZS after adult immunization. The most promising vaccines to emerge from phase 1 and 2 testing should have a clear plan to readily deploy phase 3 trials in the event of an outbreak, as was implemented for Ebola, including infant follow-up. This study of Ad26.ZIKV.001 did not evaluate safety and immunogenicity in pregnant women. However, this group is a major target for ZIKV immunization both to protect the fetus and for the transfer of antibodies that might protect against early postnatal infection. Despite substantial immune alterations during pregnancy, vaccination of pregnant women against neonatal pathogens, such as influenza and tetanus, has been highly efficiacious (9). Similar to the strategy for rubella immunization, vaccination in childhood to elicit protective immunity against congenitally transmitted pathogens in women of childbearing age would probably be the most successful approach to eliminate CZS. Yet, it is likely that late-stage