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Impact of SARS-CoV-2 vaccination of children ages 5–11 years on COVID-19 disease burden and resilience to new variants in the United States, November 2021–March 2022: A multi-model study

Background The COVID-19 Scenario Modeling Hub convened nine modeling teams to project the impact of expanding SARS-CoV-2 vaccination to children aged 5–11 years on COVID-19 burden and resilience against variant strains. Methods Teams contributed state- and national-level weekly projections of cases, hospitalizations, and deaths in the United States from September 12, 2021 to March 12, 2022. Four scenarios covered all combinations of 1) vaccination (or not) of children aged 5–11 years (starting November 1, 2021), and 2) emergence (or not) of a variant more transmissible than the Delta variant (emerging November 15, 2021). Individual team projections were linearly pooled. The effect of childhood vaccination on overall and age-specific outcomes was estimated using meta-analyses. Findings Assuming that a new variant would not emerge, all-age COVID-19 outcomes were projected to decrease nationally through mid-March 2022. In this setting, vaccination of children 5–11 years old was associated with reductions in projections for all-age cumulative cases (7.2%, mean incidence ratio [IR] 0.928, 95% confidence interval [CI] 0.880–0.977), hospitalizations (8.7%, mean IR 0.913, 95% CI 0.834–0.992), and deaths (9.2%, mean IR 0.908, 95% CI 0.797–1.020) compared with scenarios without childhood vaccination. Vaccine benefits increased for scenarios including a hypothesized more transmissible variant, assuming similar vaccine effectiveness. Projected relative reductions in cumulative outcomes were larger for children than for the entire population. State-level variation was observed. Interpretation Given the scenario assumptions (defined before the emergence of Omicron), expanding vaccination to children 5–11 years old would provide measurable direct benefits, as well as indirect benefits to the all-age U.S. population, including resilience to more transmissible variants. Funding Various (see acknowledgments).

The Lancet Regional Health - Americas↗

Consumption of baits containing raccoon pox-based plague vaccines protects black-tailed prairie dogs (Cynomys ludovicianus)

Baits containing recombinant raccoon poxvirus (RCN) expressing plague antigens (fraction 1 [F1] and a truncated form of the V protein-V307) were offered for voluntary consumption several times over the course of several months to a group of 16 black-tailed prairie dogs ( Cynomys ludovicianus ). For comparison, another group of prairie dogs ( n = 12) was injected subcutaneously (SC) (prime and boost) with 40 μg of F1-V fusion protein absorbed to alum, a vaccine-adjuvant combination demonstrated to elicit immunity to plague in mice and other mammals. Control animals received baits containing RCN without the inserted antigen ( n = 8) or injected diluent ( n = 7), and as there was no difference in their survival rates by Kaplan–Meier analysis, all of them were combined into one group in the final analysis. Mean antibody titers to Yersinia pestis F1 and V antigen increased ( p < 0.05) in the vaccinated groups compared to controls, but titers were significantly higher ( p < 0.0001) in those receiving injections of F1-V fusion protein than in those orally vaccinated with RCN-based vaccine. Interestingly, upon challenge with approximately 70,000 cfu of virulent Y. pestis , oral vaccination resulted in survival rates that were significantly higher ( p = 0.025) than the group vaccinated by injection with F1-V fusion protein and substantially higher ( p < 0.0001) than the control group. These results demonstrate that oral vaccination of prairie dogs using RCN-based plague vaccines provides significant protection against challenge at dosages that simulate simultaneous delivery of the plague bacterium by numerous flea bites.

Vector-Borne and Zoonotic Diseases↗

Oral sylvatic plague vaccine does not adequately protect prairie dogs (Cynomys spp.) for endangered black-footed ferret (Mustela nigripes) conservation

The plague bacterium Yersinia pestis is lethal to endangered black-footed ferrets ( Mustela nigripes , BFF) and the prairie dogs ( Cynomys spp., PD) on which they depend for habitat and prey. We assessed the effectiveness of an oral sylvatic plague vaccine delivered in baits to black-tailed PD ( Cynomys ludovicianus , BTPD) from 2013 to 2017 on the Charles M. Russell National Wildlife Refuge (CMR) in northcentral Montana. We permanently marked BTPD on four paired vaccine ( N = 1,349 individuals) and placebo plots ( N = 926; 7,027 total captures). We analyzed capture–recapture data under a Cormack–Jolly–Seber model to estimate annual apparent survival. Overall, survival averaged 0.05 lower on vaccine plots than on paired placebo plots. Immediately before noticeable die-offs and detecting plague on pairs CMR1 and CMR2, 89% of BTPD sampled on vaccine plots had consumed at least one bait and the immune systems (pleural) of 40% were likely boosted by consuming baits over multiple years. Survival to the following year was 0.16 and 0.05 on the vaccine plots and 0.19 and 0.06 on the placebo plots for pairs CMR1 and CMR2, respectively. These rates were markedly lower than 0.63, the overall average estimate on those same plots during the previous 3 years. PD populations subjected to such large die-offs would not be expected to sustain a BFF population. An overriding limitation to achieving sufficient protection rests with vaccine delivery constraints. Late summer/fall bait distribution results in the highest bait uptake rates. However, the PD birth pulse each spring can double the size of populations in most years, greatly reducing the proportion of vaccinates in populations and diminishing potential herd immunity benefits. In addition to nonvaccinated juveniles and PD that do not consume bait, incomplete vaccine protection and time required for immunity to develop leaves a large majority of PD populations vulnerable to plague for 6–7 months or more each year.

Montana↗

Modeling the response of an endangered rabbit population to RHDV2 and vaccination

Rabbit hemorrhagic disease virus 2 (RHDV2), recently detected in the western United States, has the potential to cause mass mortality events in wild rabbit and hare populations. Currently, few management strategies exist other than vaccination. We developed a spatially explicit model of RHDV2 for a population of riparian brush rabbits ( Sylvilagus bachmani riparius ), a subspecies of brush rabbit classified as endangered in the United States, on a subsection of the San Joaquin River National Wildlife Refuge. The goal of our model was to provide guidance regarding vaccination strategies for an endangered rabbit species. Our model predicts that increased interactions between rabbits (a proxy for landscape connectivity) and disease transmission rates among susceptible hosts (individual brush rabbits and conspecifics) have the greatest influence on the outcome of a potential vaccination campaign. Our model projects that across a range of parameter estimates (given an RHDV2 incursion), the median estimated population size with a 0%–10% vaccination rate after 1 year is 538 rabbits (95% Confidence Interval [C.I.] 69–1235), approximately 36% of the expected size of the study population of 1470 rabbits without an RHDV2 introduction. With a 10%–20%, 20%–30%, or 30%–40% vaccination rate, the median estimated population size increased to 628 rabbits (95% C.I. 130–1298), 723 rabbits (95% C.I. 198–1317), and 774 rabbits (95% C.I. 228–1410), respectively. These estimates represent 43%, 49%, and 53% of the expected population size without an RHDV2 introduction. Overall, a 1% increase in vaccination rate was associated with a six rabbit (95% C.I. 5–7) increase in total remaining population size. This result is dependent on assumptions regarding environmental transmission, home range size (and contact rates of rabbits). Given the relatively short lifespan of rabbits and the potential need for boosters, vaccination programs are most likely to be successful for small target populations where relatively high vaccination rates can be maintained.

California↗

The dose-dependent effect on protection and humoral response to a DNA vaccine against Infectious Hematopoietic Necrosis (IHN) virus in subyearling rainbow trout

A dose&ndash;response study that used the DNA vaccine pIHNw-G against infectious hematopoietic necrosis virus (IHNV) showed that complete and highly significant ( P < 0.001) protection against a virus injection challenge can be attained in subyearling rainbow trout Oncorhynchus mykiss (145&ndash;160 g, 8- to 10-months-old) 6 weeks after a single intramuscular injection with doses as low as 1 &mu;g. Complete protection was also reproducibly demonstrated at higher vaccine doses; however, no protection was observed with a 0.1-&mu;g dose. Virus-neutralizing antibody titers were detected in fish that had been vaccinated with different doses of the DNA vaccine and then sham-infected; there appeared to be a dose-dependent effect, with higher titers obtained with higher doses of vaccine. The DNA-vaccinated animals that survived virus challenge had significantly ( P < 0.05) higher neutralizing antibody titers than sham-infected, DNA-vaccinated control fish. Additionally, the titers detected in the IHN survivors exhibited a significant ( P < 0.05) dose-dependent effect, with the highest titers being present in fish that received the highest vaccine doses.

Journal of Fish Diseases↗

Efficacy of an infectious hematopoietic necrosis (IHN) virus DNA vaccine in Chinook Oncorhynchus tshawytscha and sockeye O. nerka salmon

The level of protective immunity was determined for Chinook Oncorhynchus tshawytscha and sockeye/kokanee salmon (anadromous and landlocked) O. nerka following intramuscular vaccination with a DNA vaccine against the aquatic rhabdovirus, infectious hematopoietic necrosis virus (IHNV). A DNA vaccine containing the glycoprotein gene of IHNV protected Chinook and sockeye/kokanee salmon against waterborne or injection challenge with IHNV, and relative percent survival (RPS) values of 23 to 86% were obtained under a variety of lethal challenge conditions. Although this is significant protection, it is less than RPS values obtained in previous studies with rainbow trout (O. mykiss). In addition to the variability in the severity of the challenge and inherent host susceptibility differences, it appears that use of a cross-genogroup challenge virus strain may lead to reduced efficacy of the DNA vaccine. Neutralizing antibody titers were detected in both Chinook and sockeye that had been vaccinated with 1.0 and 0.1 ??g doses of the DNA vaccine, and vaccinated fish responded to viral challenges with higher antibody titers than mock-vaccinated control fish. ?? Inter-Research 2005.

Diseases of Aquatic Organisms↗

Apparent field safety of a raccoon poxvirus-vectored plague vaccine in free-ranging prairie dogs ( Cynomys spp.), Colorado, USA

Prairie dogs ( Cynomys spp.) suffer high rates of mortality from plague. An oral sylvatic plague vaccine using the raccoon poxvirus vector (designated RCN-F1/V307) has been developed for prairie dogs. This vaccine is incorporated into palatable bait along with rhodamine B as a biomarker. We conducted trials in August and September 2012 to demonstrate uptake and apparent safety of the RCN-F1/V307 vaccine in two prairie dog species under field conditions. Free-ranging prairie dogs and other associated small rodents readily consumed vaccine-laden baits during field trials with no apparent adverse effects; most sampled prairie dogs (90%) and associated small rodents (78%) had consumed baits. Visual counts of prairie dogs and their burrows revealed no evidence of prairie dog decline after vaccine exposure. No vaccine-related morbidity, mortality, or gross or microscopic lesions were observed. Poxviruses were not isolated from any animal sampled prior to bait distribution or on sites that received placebo baits. We isolated RCN-F1/V307 from 17 prairie dogs and two deer mice ( Peromyscus maniculatus ) captured on sites where vaccine-laden baits were distributed. Based on these findings, studies examining the utility and effectiveness of oral vaccination to prevent plague-induced mortality in prairie dogs and associated species are underway.

Colorado↗

Responses of juvenile black-tailed prairie dogs (Cynomys ludovicianus) to a commercially produced oral plague vaccine delivered at two doses

We confirmed safety and immunogenicity of mass-produced vaccine baits carrying an experimental, commercial-source plague vaccine (RCN-F1/V307) expressing Yersinia pestis V and F1 antigens. Forty-five juvenile black-tailed prairie dogs ( Cynomys ludovicianus ) were randomly divided into three treatment groups ( n =15 animals/group). Animals in the first group received one standard-dose vaccine bait (5×10 7 plaque-forming units [pfu]; STD). The second group received a lower-dose bait (1×10 7 pfu; LOW). In the third group, five animals received two standard-dose baits and 10 were left untreated but in contact. Two vaccine-treated and one untreated prairie dogs died during the study, but laboratory analyses ruled out vaccine involvement. Overall, 17 of 33 (52%; 95% confidence interval for binomial proportion [bCI] 34−69%) prairie dogs receiving vaccine-laden bait showed a positive anti-V antibody response on at least one sampling occasion after bait consumption, and eight (24%; bCI 11–42%) showed sustained antibody responses. The STD and LOW groups did not differ ( P ≥0.78) in their proportions of overall or sustained antibody responses after vaccine bait consumption. Serum from one of the nine (11%; bCI 0.3–48%) surviving untreated, in-contact prairie dogs also had detectable antibody on one sampling occasion. We did not observe any adverse effects related to oral vaccination.

Journal of Wildlife Diseases↗

Whooping crane titers to eastern equine encephalitis vaccinations

In 1984 an epizootic of eastern equine encephalitis (EEE) virus killed 7 of 39 (18%) whooping cranes in captivity at the Patuxent Wildlife Research Center in Laurel, Maryland, USA. Since that time whooping cranes have been vaccinated with a human EEE vaccine. This vaccine was unavailable for several years, necessitating use of an equine vaccine in the cranes. This study compared the antibody titers measured for three years using the human vaccine with those measured for two years using the equine form. Whooping cranes developed similarly elevated titers in one year using the human vaccine and both years using the equine vaccine. However, in two years where the human vaccine was used, the whooping cranes developed significantly lower titers compared to other years.

Book chapter↗

Use of an inactivated eastern equine encephalitis virus vaccine in cranes

An unprecedented outbreak of fatal eastern equine encephalitis (EEE) virus occurred during the late summer and fall of 1984 in endangered whooping cranes (Grus americana) at the Patuxent Wildlife Research Center, Laurel, Maryland. As part of efforts to prevent future epizootics of EEE. studies were conducted to evaluate the antibody response of cranes following vaccination with a formalin-inactivated EEE virus vaccine. Viral specific neutralizing antibody was elicited in sandhill cranes (Grus canadensis) and whooping cranes following 1M inoculation with the vaccine. Among the 1M-inoculated cranes, peak antibody titers of 1:80 on days 30 to 60 had waned to undetectable levels by days 90 to 120. Although the initial titers were not increased by the first booster dose, the duration of the antibody was extended considerably. Whooping cranes, receiving vaccine 6 months after their first vaccination, developed titers of 1:80 to 1:320 by day 30. At 45 days after the final vaccination, these titers had dropped to 1:10 to 1:160. Cranes with preexisting EEE virus antibody, apparently reflecting natural infection, exhibited an anamnestic response indicated by a rapid increase and sustained high antibody titer. Even though EEE virus vaccine induced neutralizing antibody and produced no adverse side effects, further studies will be required to assess the significance of this response as a strategy for protecting whooping cranes against natural EEE virus infection. The loss of captive whooping cranes to the EEE virus presented a previously unrecognized risk and obstacle to recovery of this species. Not only was, there a setback in the captive breeding and reintroduction program for the whooping crane, but, because of the susceptibility of the species to the EEE virus. establishment of additional crane populations may be more complicated than initially envisioned. However, through continued surveillance, serological monitoring, and vaccination activities, we are confident that the impact of EEE virus on whooping crane recovery can be overcome to the ultimate benefit of this endangered species.

American Association of Zoo Veterinarians, Annual ↗

Impact of molecular modifications on the Immunogenicity and efficacy of recombinant raccoon poxvirus-vectored rabies vaccine candidates in mice

Rabies is an ancient disease that is responsible for approximately 59,000 human deaths annually. Bats (Order Chiroptera ) are thought to be the original hosts of rabies virus (RABV) and currently account for most rabies cases in wildlife in the Americas. Vaccination is being used to manage rabies in other wildlife reservoirs like fox and raccoon, but no rabies vaccine is available for bats. We previously developed a recombinant raccoonpox virus (RCN) vaccine candidate expressing a mosaic glycoprotein (MoG) gene that protected mice and big brown bats when challenged with RABV. In this study, we developed two new recombinant RCN candidates expressing MoG (RCN-tPA-MoG and RCN-SS-TD-MoG) with the aim of improving RCN-MoG. We assessed and compared in vitro expression, in vivo immunogenicity, and protective efficacy in vaccinated mice challenged intracerebrally with RABV. All three candidates induced significant humoral immune responses, and inoculation with RCN-tPA-MoG or RCN-MoG significantly increased survival after RABV challenge. These results demonstrate the importance of considering molecular elements in the design of vaccines, and that vaccination with either RCN-tPA-MoG or RCN-MoG confers adequate protection from rabies infection, and either may be a sufficient vaccine candidate for bats in future work.

Vaccines↗

Assessment of a strain 19 brucellosis vaccination program in elk

Zoonotic diseases in wildlife present substantial challenges and risks to host populations, susceptible domestic livestock populations, and affected stakeholders. Brucellosis, a disease caused by the bacterium Brucella abortus , is endemic among elk ( Cervus canadensis ) attending winter feedgrounds and adjacent areas of western Wyoming, USA. To minimize transmission of brucellosis from elk to elk and elk to livestock, managers initiated a B. abortus strain 19 ballistic vaccination program in 1985. We used brucellosis prevalence (1971–2015) and reproductive outcome (2006–2015) data collected from female elk attending feedgrounds to assess efficacy of the strain 19 program while controlling for potentially confounding factors such as site and age. From our generalized linear models, we found that seroprevalence of brucellosis was 1) not lower following inception of vaccination; 2) not inversely associated with proportion of juveniles vaccinated over time; 3) not inversely associated with additional yearlings and adults vaccinated over time; and 4) associated more with feeding end-date than proportion of juveniles vaccinated. Using vaginal implant transmitters in adult females that were seropositive for brucellosis, we found little effect of vaccination coverage at reducing reproductive failures (i.e., abortion or stillbirth). Because we found limited support for efficacy of the strain 19 program, we support research to develop an oral vaccine and suggest that continuing other spatio-temporal management actions will be most effective to minimize transmission of brucellosis and reduce dependency of elk on supplemental winter feeding.

Idaho, Wyoming↗

Protective efficacy of a recombinant subunit West Nile virus vaccine in domestic geese (Anser anser)

Introduction of the West Nile virus (WNV) to Hawai'i will undoubtedly devastate many populations of critically endangered avian species indigenous to Hawai'i. The protective efficacy of a protein-based WNV subunit vaccine formulated with adjuvant was evaluated in domestic geese as a surrogate species for the endangered Ne??ne??, the state bird of Hawai'i. Prevention of viremia following viral infection of vaccinated birds was used as the clinical endpoint of protection. ELISA and plaque reduction neutralization tests demonstrate that significant levels of vaccine antigen-specific antibody were produced in groups of birds vaccinated with 5 or 10 ??g of the WN-80E antigen formulated with ISA720 adjuvant. Moreover, after challenge with WNV, no viremia was detected in vaccinated birds, whereas viremia was detected up to 4 days after and virus was detected by oral swab for 6 days after infection among control groups. Safe and effective vaccination of managed or captive endangered bird populations will protect species with critically low numbers that could not survive the added mortality of introduced disease. ?? 2008 Elsevier Ltd.

Hawai'i↗

Further development of raccoon poxvirus-vectored vaccines against plague (Yersinia pestis)

In previous studies, we demonstrated protection against plague in mice and prairie dogs using a raccoon pox (RCN) virus-vectored vaccine that expressed the F1 capsular antigen of Yersinia pestis. In order to improve vaccine efficacy, we have now constructed additional RCN-plague vaccines containing two different forms of the lcrV (V) gene, including full-length (Vfull) and a truncated form (V307). Mouse challenge studies with Y. pestis strain CO92 showed that vaccination with a combination of RCN-F1 and the truncated V construct (RCN-V307) provided the greatest improvement (P = 0.01) in protection against plague over vaccination with RCN-F1 alone. This effect was mediated primarily by anti-F1 and anti-V antibodies and both contributed independently to increased survival of vaccinated mice.

Vaccine↗

Vaccination against bacterial kidney disease

Bacterial kidney disease (BKD) of salmonid fishes, caused by Renibacterium salmoninarum , has been recognized as a serious disease in salmonid fishes since the 1930s. This chapter discusses the occurrence and significance, etiology, and pathogenesis of BKD. It then describes the different vaccination procedures and the effects and side-effects of vaccination. Despite years of research, however, only a single vaccine has been licensed for prevention of BKD, and has demonstrated variable efficacy. Therefore, in addition to a presentation of the current status of BKD vaccination, a discussion of potential future directions for BKD vaccine development is included in the chapter. This discussion is focused on the unique characteristics of R. salmoninarum and its biology, as well as aspects of the salmonid immune system that might be explored specifically to develop more effective vaccines for BKD prevention.

Book chapter↗

Fish DNA vaccine against infectious hematopoietic necrosis virus: efficacy of various routes of immunization

The DNA vaccine, pIHNVw-G, contains the gene for the glycoprotein (G) of the rhabdovirus infectious hematopoietic necrosis virus (IHNV), a major pathogen of salmon and trout. The relative efficacy of various routes of immunisation with pIHNVw-G was evaluated using 1.8 g rainbow trout fry vaccinated via intramuscular injection, scarification of the skin, intraperitoneal injection, intrabuccal administration, cutaneous particle bombardment using a gene gun, or immersion in water containing DNA vaccine-coated beads. Twenty-seven days after vaccination neutralising antibody titres were determined, and 2 days later groups of vaccinated and control unvaccinated fish were subjected to an IHNV immersion challenge. Results of the virus challenge showed that the intramuscular injection and the gene gun immunisation induced protective immunity in fry, while intraperitoneal injection provided partial protection. Neutralising antibodies were not detected in sera of vaccinated fish regardless of the route of immunisation used, suggesting that cell mediated immunity may be at least partially responsible for the observed protection.

Fish and Shellfish Immunology↗

Analysis of DNA-vaccinated fish reveals viral antigen in muscle, kidney, and thymus, and transient histopathologic changes

A highly efficacious DNA vaccine against a fish rhabdovirus, infectious hematopoietic necrosis virus (IHNV), was used in a systematic study to analyze vaccine tissue distribution, persistence, expression patterns, and histopathologic effects. Vaccine plasmid pIHNw-G, containing the gene for the viral glycoprotein, was detected immediately after intramuscular injection in all tissues analyzed, including blood, but at later time points was found primarily in muscle tissue, where it persisted to 90 days. Glycoprotein expression was detected in muscle, kidney, and thymus tissues, with levels peaking at 14 days and becoming undetectable by 28 days. Histologic examination revealed no vaccine-specific pathologic changes at the standard effective dose of 0.1 ??g DNA per fish, but at a high dose of 50 ??g an increased inflammatory response was evident. Transient damage associated with needle injection was localized in muscle tissue, but by 90 days after vaccination no damage was detected in any tissue, indicating the vaccine to be safe and well tolerated. ?? Springer Science+Business Media, Inc. 2005.

Marine Biotechnology↗

Immunostimulants, adjuvants, and vaccine carriers in fish: Applications to aquaculture

Use of immunostimulants, adjuvants, and vaccine carriers in fish culture offers a wide range of attractive methods for inducing and building up protection against diseases. Immunostimulants and adjuvants can be administered before, with, or after vaccines to amplify the specific immune response generating elevations of circulating antibody titers and numbers of plaque-forming cells. Special applications of immunostimulants include assisting shower or other regimens to increase topical uptake of vaccines. In addition, immunostimulants may be used alone, inducing elevated activities in the nonspecific defense mechanisms such as increased oxidative activity of neutrophils, augmented engulfment activity of phagocytic cells, or potentiating cytotoxic cells. In cases where disease outbreaks are cyclical and can be predicted, losses may be reduced by elevating the nonspecific defense mechanisms, and the immunostimulants may be used in anticipation of events to prevent losses from diseases. Complete Freund's adjuvant was one of the first immunostimulants used in animals to elevate the specific immune response, and it has also been successfully used in conjunction with injection of fish bacterins. Other adjuvants, immunostimulants, and biological response modifiers that have been used in fisheries research include levamisole, salt baths, and bacterial lipopolysaccharides. Vaccines have been adsorbed to inert particles, such as bentonite on latex beads, to carry the immunogens to maximize in vivo uptake for bath immunization and to facilitate in vitro phagocytosis. Each substance presents special problems in timing and method of administration (injection, immersion, oral—by feed—or flush treatments), dosage adjustments for size and fish species, storage stability, and cost. An additional consideration is that the nonspecific defense mechanisms and immune responses in fish are highly variable among individuals and statistical validation requires appropriate sample numbers and carefully controlled experiments. This article reviews the literature and present concepts of use of immunostimulants, adjuvants, and vaccine carriers in fish. Cautions for use are noted, as some of these potent substances can suppress or alter biological pathways if used inappropriately. Recent research, defining pathways of the action of immunostimulants, adjuvants, and vaccine carriers, helps explain how these substances activate the protective mechanisms in fish. In addition, immunostimulants used alone hold tremendous potential for use in fish farms, hatcheries, and aquaculture facilities to reduce losses from infectious diseases. Research on the immunostimulant, levamisole, and the light oil adjuvants for use in food fish is in progress. Applications for use of these immunostimulants are proposed.

Annual Review of Fish Diseases↗