Human Herd Immunity Research Articles

The Natural History of SARS-CoV-2-Incurred Disease: From Infection to Long COVID

The coronavirus SARS-CoV-2 is the causative pathogen of the COVID-19 pandemic that has been causing global upheaval since 2019. The widespread administration of vaccines has partially deterred the spread of SARS-CoV-2, yet the virus is mutating its genome to reduce its antigenicity and evade the human herd immunity. It seems that SARS-CoV-2 will co-exist with the human population for many decades to come. While most infected individuals only experience mild to moderate symptoms, some develop severe pulmonary and systemic disease that can result in hospitalization or even death. The natural history model of SARS-CoV-2 infection has been proposed which includes three sequential stages: the early infection stage, pulmonary stage, and hyper-inflammatory stage. Recently, it has been observed that many people who recovered from an acute infection still experience persistent symptoms for weeks or months, a condition known as long COVID. Furthermore, some COVID-19 patients display escalated rates of both macro- and micro-thrombosis due to endotheliopathy. Hence, we added the thrombosis and convalescent stages to the natural history model, encompassing the entire period from early infection to long COVID. The early infection stage is characterized by symptomatic or asymptomatic elevation of viral titers. Some patients progress to the pulmonary stage characterized by opacities in chest X-rays and computed tomography. The thrombosis stage is characterized by heightened rates of pulmonary thrombosis and consistently elevated D-dimer levels. The hyper-inflammatory stage is characterized by storms of cytokines, such as IL-6, IL-17, and interferons, which is a systemic effect. In the convalescent stage, some people recover completely, while others suffer from long COVID with persistent symptoms such as fatigue, shortness of breath, or brain fog. The natural history model of SARS-CoV-2 infection can be used to elucidate treatment and care.

Immunogenicity and protective efficacy of a DNA vaccine inducing optimal expression of the SARS-CoV-2 S gene in hACE2 mice.

The wide spread of coronavirus disease 2019 (COVID-19) has significantly threatened public health. Human herd immunity induced by vaccination is essential to fight the epidemic. Therefore, highly immunogenic and safe vaccines are necessary to control SARS-CoV-2, whose S protein is the antigenic determinant responsible for eliciting antibodies that prevent viral entry and fusion. In this study, we developed a SARS-CoV-2 DNA vaccine expressing the S protein, named pVAX-S-OP, which was optimized according to the human-origin codon preference and using polyinosinic–polycytidylic acid as an adjuvant. pVAX-S-OP induced specific antibodies and neutralizing antibodies in BALB/c and hACE2 transgenic mice. Furthermore, we observed 1.43-fold higher antibody titers in mice receiving pVAX-S-OP plus adjuvant than in those receiving pVAX-S-OP alone. Interferon gamma production in the pVAX-S-OP-immunized group was 1.58 times (CD3+CD4+IFN-gamma+) and 2.29 times (CD3+CD8+IFN-gamma+) lower than that in the pVAX-S-OP plus adjuvant group but higher than that in the control group. The pVAX-S-OP vaccine was also observed to stimulate a Th1-type immune response. When, hACE2 transgenic mice were challenged with SARS-CoV-2, qPCR detection of N and E genes showed that the viral RNA loads in pVAX-S-OP-immunized mice lung tissues were 104 times and 106 times lower than those of the PBS control group, which shows that the vaccine could reduce the amount of live virus in the lungs of hACE2 mice. In addition, pathological sections showed less lung damage in the pVAX-S-OP-immunized group. Taken together, our results demonstrated that pVAX-S-OP has significant immunogenicity, which provides support for developing SARS-CoV-2 DNA candidate vaccines.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00705-022-05562-z.

Immunities of the Herd in Peace, War, and COVID-19.

Intermittently, the concept of herd immunity has been a potent, if sometimes ambiguous and controversial, means of framing the global response to the COVID-19 pandemic and envisaging its end. Realizing the full meaning of human herd immunity requires further attention to its connections after World War I with British social theory. Distracted by "obvious" yet unsubstantiated correspondences with veterinary research, historians of the concept have not engaged with the more proximate influence of discussions of social psychology and group dynamics on postwar epidemiology. Understanding the openness of early 20th century epidemiology to social thought deepens our appreciation of the significance of herd or population immunity, as well as suggests new avenues for exchange between public health and contemporary social sciences. (Am J Public Health. 2022;112(10):1465-1470. https://doi.org/10.2105/AJPH.2022.306931).

The genetic characterization of hemagglutinin (HA), neuraminidase (NA) and polymerase acidic (PA) genes of H3N2 influenza viruses circulated in Guangdong Province of China during 2019-2020.

The evolution of seasonal influenza viruses, which can cause virus antigenic drift to escape human herd immunity, is a significant public health problem. Here, we obtained hemagglutinin (HA), neuraminidase (NA), and polymerase acidic protein (PA) the gene sequences of 84 influenza virus isolates collected in Guangdong Province during the 2019-2020 influenza season. Phylogenetic analyses revealed all these isolates were genetically similar to the viruses of clade 3C2a A1b, specifically those within subclades of A1b 137F (59 cases), A1b 186D (19 cases), and A1b 94N (6 cases). The influenza virus isolates were distinct from the World Health Organization recommended influenza A vaccine virus for the 2019-2020 Northern Hemisphere season (A/Kansas/14/2017; H3N2). Phylogenies inferred from the individual gene segment sequences revealed that one reassortment event occurred among these clades. The genetic variation involved mutations within viral antigenic epitopes and two N-glycosylation site alterations. The novel mutation sites of G202D and D206N in the HA gene, E344K in the NA gene, and K626R in the PA gene which may affect the spread of the virus were observed. We investigated the evolution of these genes and found that the HA and NA genes were under greater pressure than PA gene. Mutations associated with conferring resistance to NA inhibitors or baloxavir acid were not found. Our results suggest that a rapid evolution of the H3N2 influenza virus occurred, thus continuous monitoring is critical for establishing appropriate vaccine formulations or drug delivery for targeting influenza.

An RBD-Based Diagnostic Method Useful for the Surveillance of Protective Immunity against SARS-CoV-2 in the Population.

After more than two years, the COVID-19 pandemic is still ongoing and evolving all over the world; human herd immunity against SARS-CoV-2 increases either by infection or by unprecedented mass vaccination. A substantial change in population immunity is expected to contribute to the control of transmission. It is essential to monitor the extension and duration of the population’s immunity to support the decisions of health authorities in each region and country, directed to chart the progressive return to normality. For this purpose, the availability of simple and cheap methods to monitor the levels of relevant antibodies in the population is a widespread necessity. Here, we describe the development of an RBD-based ELISA for the detection of specific antibodies in large numbers of samples. The recombinant expression of an RBD-poly-His fragment was carried out using either bacterial or eukaryotic cells in in vitro culture. After affinity chromatography purification, the performance of both recombinant products was compared by ELISA in similar trials. Our results showed that eukaryotic RBD increased the sensitivity of the assay. Interestingly, our results also support a correlation of the eukaryotic RBD-based ELISA with other assays aimed to test for neutralizing antibodies, which suggests that it provides an indication of protective immunity against SARS-CoV-2.

A Complex Dance: Measuring the Multidimensional Worlds of Influenza Virus Evolution and Anti-Influenza Immune Responses.

The human antibody response to influenza virus infection or vaccination is as complicated as it is essential for protection against flu. The constant antigenic changes of the virus to escape human herd immunity hinder the yearly selection of vaccine strains since it is hard to predict which virus strains will circulate for the coming flu season. A “universal” influenza vaccine that could induce broad cross-influenza subtype protection would help to address this issue. However, the human antibody response is intricate and often obscure, with factors such as antigenic seniority or original antigenic sin (OAS), and back-boosting ensuring that each person mounts a unique immune response to infection or vaccination with any new influenza virus strain. Notably, the effects of existing antibodies on cross-protective immunity after repeated vaccinations are unclear. More research is needed to characterize the mechanisms at play, but traditional assays such as hemagglutinin inhibition (HAI) and microneutralization (MN) are excessively limited in scope and too resource-intensive to effectively meet this challenge. In the past ten years, new multiple dimensional assays (MDAs) have been developed to help overcome these problems by simultaneously measuring antibodies against a large panel of influenza hemagglutinin (HA) proteins with a minimal amount of sample in a high throughput way. MDAs will likely be a powerful tool for accelerating the study of the humoral immune response to influenza vaccination and the development of a universal influenza vaccine.

Molecular Dynamics Simulation of the Influenza A(H3N2) Hemagglutinin Trimer Reveals the Structural Basis for Adaptive Evolution of the Recent Epidemic Clade 3C.2a

Influenza A(H3N2) has been a major cause of seasonal influenza in humans since 1968, and has evolved by antigenic drift under the constantly changing human herd immunity. Increasing evidence suggests that the antigenic change occasionally occurred concomitant with the alterations of the N-glycosylation site profile and hemagglutination activity of the virion surface protein hemagglutinin (HA). However, the structural basis of these changes remains largely unclear. To address this issue, we performed molecular dynamics simulations of the glycosylated HA trimers of the A(H3N2), which has a novel pattern of Asn-X-Ser/Thr sequons unique in the new A(H3N2) epidemic clade 3C.2a and is characterized by attenuated ability to agglutinate nonhuman erythrocytes. Comparison of the equilibrated structures of the glycosylated HA trimers with and without the 3C.2a-specific mutations reveals that the mutations could induce a drastic reduction in the apical space for the ligand binding via glycan-shield rearrangement. The results suggest that the 3C.2a strain has evolved an HA structure that is advantageous for evading pre-existing antibodies, while also increasing the ligand binding specificity. These findings have structural implications for our understanding of the phenotypic changes, evolution, and fate of influenza A(H3N2).

Evolutionary Constraints on the Norovirus Pandemic Variant GII.4_2006b over the Five-Year Persistence in Japan.

Norovirus GII.4 is a major cause of global outbreaks of viral gastroenteritis in humans, and has evolved by antigenic changes under the constantly changing human herd immunity. Major shift in the pandemic GII.4 strain periodically occurs concomitant with changes in the antigenic capsid protein VP1. However, how the newly emerged strain evolves after the onset of pandemic remains unclear. To address this issue, we examined molecular evolution of a pandemic lineage, termed the GII.4_2006b, by using the full-length viral genome and VP1 sequences (n = 317) from stools collected at 20 sites in Japan between 2006 and 2011. Phylogenetic tree showed a radial diversification of the genome sequences of GII.4_2006b, suggesting a rapid genetic diversification of the GII.4_2006b population from a few ancestral variants. Impressively, amino acid sequences of the variable VP1 in given seasons remained as homogeneous as those of viral enzymes under annual increase in the nucleotide diversity in the VP1 coding region. The Hamming distances between the earliest and subsequent variants indicate strong constraints on amino acid changes even for the highly variable P2 subdomain. These results show the presence of evolutionary constraints on the VP1 protein and viral enzymes, and suggest that these proteins gain near maximal levels of fitness benefits in humans around the onset of the outbreaks. These findings have implications for our understanding of molecular evolution, mechanisms of the periodic shifts in the pandemic NoV GII.4 strains, and control of the NoV GII.4 pandemic strain.

Resurgence of West Nile Virus in 2012: Lack of Evidence for Viral Genetic Determinants

Since the introduction into North America in 1999 of West Nile virus (WNV) and its subsequent dramatic spread across the United States and Canada, human cases of WNV infection declined from their 2003 peak of 9,862 to only 712 cases and 43 fatalities confirmed in 2011 (http://www.cdc .gov/ncidod/dvbid/westnile/index.htm). The reasons for this decline remain unclear because avian amplification host and human herd immunity remains low in most regions and WNV continues to circulate in most areas of the United States. However, last year an unexpected resurgence in West Nile fever and encephalitis cases occurred; a total of 5,674 human cases was detected in the United States, with 286 deaths, making 2012 the deadliest year yet. The epidemic was focused in the central part of the United States, with Texas reporting 1,739 human infections and 89 deaths, or about 33% of the national total and more than three times the number of any other state. Within Texas, Dallas County was the epicenter, with 398 human infections and 20 deaths. The reasons for this dramatic resurgence in WNV infections are not clear; however, several factors could be involved ranging from increased enzootic bird-mosquito-bird circulation, resulting in more human spillover infections, to increased human virulence. In this issue, Duggal and others report complete genomic sequences of 17 WNV isolates from several regions of Texas and phylogenetic studies to determine if viral genetic changes might have been responsible for the resurgence in human cases. Two distinct WNV genotypes were identified, and both circulated in the Dallas and Houston regions where disease incidence differed markedly (about four times higher in Dallas). Importantly, no signs of adaptive evolution that could have resulted in more efficient infection of mosquitoes or birds were identified in any of the recent WNV strains. These results, along with epidemiological analyses, suggest that the 2012 resurgence in the Dallas area resulted from an increase in transmission by mosquitoes from birds to humans (spillover infections), rather than an increase in WNV neuroinvasiveness. Unusually high summer temperatures in the Dallas area, perhaps combined with ecological changes affecting mosquito or avian populations, probably played important roles in driving the 2012 outbreak. These critical findings presented by Duggal and others 1 and the magnitude of the 2012 West Nile encephalitis epidemic underscore the importance of a better understanding of how WNV, other arboviruses, and vector-borne diseases in general will respond to climate and anthropogenic ecological changes that now appear inevitable. Rising temperatures exert a wide variety of complex effects on mosquito survival, reproduction, and behavior. Because temperature also influences vector infection, dissemination, and transmission of arboviruses, often in unpredictable ways, we remain unable to anticipate the effects of global warming on arboviral disease. Droughts, which are predicted to increase in some regions of the United States and elsewhere, can also have dramatic impacts on mosquito populations, especially on West Nile mosquito vectors because of their affinity for standing, highly polluted water and to irrigated agricultural lands. Drought conditions can also concentrate avian amplifying hosts in wetter locations amenable to mosquito transmission of WNV. Thus, rigorous experimental and modeling studies are needed to improve the ability of our public health systems to anticipate and respond to the effects of climate change and its influences on vector-borne pathogens such as WNV.

Emergence of New Pandemic GII.4 Sydney Norovirus Strain Correlates With Escape From Herd Immunity

GII.4 noroviruses are a significant source of acute gastroenteritis worldwide, causing the majority of human norovirus outbreaks. Evolution of the GII.4 major capsid protein occurs rapidly, resulting in the emergence of new strains that produce successive waves of pandemic disease. A new pandemic isolate, GII.4 2012 Sydney, largely replaced previously circulating strains in late 2012. We compare the antigenic properties of GII.4 2012 Sydney with previously circulating strains. To determine whether GII.4-2012 Sydney is antigenically different from recently circulating strains GII.4-2006 Minerva and GII.4-2009 New Orleans in previously identified blockade epitopes, we compared reactivity and blockade profiles of GII.4-2006, GII.4-2009, and GII.4-2012 virus-like particles in surrogate neutralization/blockade assays using monoclonal antibodies and human polyclonal sera. Using monoclonal antibodies that map to known blockade epitopes in GII.4-2006 and GII.4-2009 and human outbreak polyclonal sera, we demonstrate either complete loss or significantly reduced reactivity and blockade of GII.4.2012 compared to GII.4-2006 and GII.4-2009. GII.4-2012 Sydney is antigenically different from GII.4-2006 Minerva and GII.4-2009 New Orleans in at least 2 key blockade epitopes. Viral evolution in key potential neutralization epitopes likely allowed GII.4-2012 to escape from human herd immunity and emerge as the new predominant strain.

Norovirus Immunity and the Great Escape

Noroviruses (NoVs), members of the Calicivirus family, are small, positive-polarity RNA viruses and the most important cause of human foodborne viral gastroenteritis worldwide. These viruses cause gastrointestinal disease, resulting in recurrent bouts of vomiting and diarrhea that typically last 24–48 hours. NoVs are transmitted via the fecal–oral route, most commonly through infected food or water or person-to-person contact, and result in 267 million infections [1] and over 200,000 deaths each year, mostly in infants and the elderly [2]. Vaccines and therapeutics are under development but face considerable challenges as there is no cell-culture system or small-animal model for human disease, and these viruses are highly heterogeneous and undergo antigenic variation in response to human herd immunity, further complicating our understanding of the complex immune interactions that regulate susceptibility and disease. Despite these limitations, considerable progress has been made in understanding NoV adaptive immunity. This article discusses our current understanding of virus–host immune interactions that regulate host susceptibility, virus evolution, and protective immunity. We focus on virion structure, serologic relationships among strains, molecular mechanisms governing the changing antigenic landscape of human NoVs over time, cellular immunity, and relationships between human herd immunity, antigenic variation, and histoblood group antigen (HBGA) recognition, which are predicted to drive the emergence of new outbreak strains that target different human populations and/or afford escape from protective herd immunity. We discuss the implications of these observations on future vaccine design. Specific Host and Virus Genetic Factors Influence NoV Susceptibility, Evolution, and Immunity

Genetic Mapping of a Highly Variable Norovirus GII.4 Blockade Epitope: Potential Role in Escape from Human Herd Immunity

Genetic Mapping of a Highly Variable Norovirus GII.4 Blockade Epitope: Potential Role in Escape from Human Herd Immunity

Genetic Mapping of a Highly Variable Norovirus GII.4 Blockade Epitope: Potential Role in Escape from Human Herd Immunity

Noroviruses account for 96% of viral gastroenteritis cases worldwide, with GII.4 strains responsible >80% of norovirus outbreaks. Histo-blood group antigens (HBGAs) are norovirus binding ligands, and antigenic and preferential HBGA binding profiles vary over time as new GII.4 strains emerge. The capsid P2 subdomain facilitates HBGA binding, contains neutralizing antibody epitopes, and likely evolves in response to herd immunity. To identify amino acids regulating HBGA binding and antigenic differences over time, we created chimeric virus-like particles (VLPs) between the GII.4-1987 and GII.4-2006 strains by exchanging amino acids in putative epitopes and characterized their antigenic and HBGA binding profiles using anti-GII.4-1987 and -2006 mouse monoclonal antibodies (MAbs) and polyclonal sera, 1988 outbreak human sera, and synthetic HBGAs. The exchange of amino acids 393 to 395 between GII.4-1987 and GII.4-2006 resulted in altered synthetic HBGA binding compared to parental strains. Introduction of GII.4-1987 residues 294, 297 to 298, 368, and 372 (epitope A) into GII.4-2006 resulted in reactivity with three anti-GII.4-1987 MAbs and reduced reactivity with four anti-GII.4-2006 MAbs. The three anti-GII.4-1987 MAbs also blocked chimeric VLP-HBGA interaction, while an anti-GII.4-2006 blocking antibody did not, indicating that epitope A amino acids comprise a potential neutralizing epitope for GII.4-1987 and GII.4-2006. We also tested GII.4-1987-immunized mouse polyclonal sera and 1988 outbreak human sera for the ability to block chimeric VLP-HBGA interaction and found that epitope A amino acids contribute significantly to the GII.4-1987 blockade response. Our data provide insights that help explain the emergence of new GII.4 epidemic strains over time, may aid development of norovirus therapeutics, and may help predict the emergence of future epidemic strains.

The impact of antigenic drift of influenza A virus on human herd immunity: Sero-epidemiological study of H1N1 in healthy Thai population in 2009

To examine the effect of the antigenic drift of H1N1 influenza viruses on herd immunity, neutralization antibodies from 744 sera from Thai healthy volunteers in 2008–2009, who had not been vaccinated for at least the last 5 years, were investigated by microneutralization (MN) and hemagglutination inhibition (HI) assays. Significantly higher MN titers were observed for the H1N1 Thai isolate in 2006 than in 2008. The results indicate that the antigenically drifted virus effectively escaped herd immunity. Since the low neutralization activity of herd immunity against drifted viruses is an important factor for viruses to spread efficiently, continuous sero-epidemiological study is required for public health.

Mechanisms of GII.4 Norovirus Persistence in Human Populations

BackgroundNoroviruses are the leading cause of viral acute gastroenteritis in humans, noted for causing epidemic outbreaks in communities, the military, cruise ships, hospitals, and assisted living communities. The evolutionary mechanisms governing the persistence and emergence of new norovirus strains in human populations are unknown. Primarily organized by sequence homology into two major human genogroups defined by multiple genoclusters, the majority of norovirus outbreaks are caused by viruses from the GII.4 genocluster, which was first recognized as the major epidemic strain in the mid-1990s. Previous studies by our laboratory and others indicate that some noroviruses readily infect individuals who carry a gene encoding a functional alpha-1,2-fucosyltransferase (FUT2) and are designated “secretor-positive” to indicate that they express ABH histo-blood group antigens (HBGAs), a highly heterogeneous group of related carbohydrates on mucosal surfaces. Individuals with defects in the FUT2 gene are termed secretor-negative, do not express the appropriate HBGA necessary for docking, and are resistant to Norwalk infection. These data argue that FUT2 and other genes encoding enzymes that regulate processing of the HBGA carbohydrates function as susceptibility alleles. However, secretor-negative individuals can be infected with other norovirus strains, and reinfection with the GII.4 strains is common in human populations. In this article, we analyze molecular mechanisms governing GII.4 epidemiology, susceptibility, and persistence in human populations.Methods and FindingsPhylogenetic analyses of the GII.4 capsid sequences suggested an epochal evolution over the last 20 y with periods of stasis followed by rapid evolution of novel epidemic strains. The epidemic strains show a linear relationship in time, whereby serial replacements emerge from the previous cluster. Five major evolutionary clusters were identified, and representative ORF2 capsid genes for each cluster were expressed as virus-like particles (VLPs). Using salivary and carbohydrate-binding assays, we showed that GII.4 VLP-carbohydrate ligand binding patterns have changed over time and include carbohydrates regulated by the human FUT2 and FUT3 pathways, suggesting that strain sensitivity to human susceptibility alleles will vary. Variation in surface-exposed residues and in residues that surround the fucose ligand interaction domain suggests that antigenic drift may promote GII.4 persistence in human populations. Evidence supporting antigenic drift was obtained by measuring the antigenic relatedness of GII.4 VLPs using murine and human sera and demonstrating strain-specific serologic and carbohydrate-binding blockade responses. These data suggest that the GII.4 noroviruses persist by altering their HBGA carbohydrate-binding targets over time, which not only allows for escape from highly penetrant host susceptibility alleles, but simultaneously allows for immune-driven selection in the receptor-binding region to facilitate escape from protective herd immunity.ConclusionsOur data suggest that the surface-exposed carbohydrate ligand binding domain in the norovirus capsid is under heavy immune selection and likely evolves by antigenic drift in the face of human herd immunity. Variation in the capsid carbohydrate-binding domain is tolerated because of the large repertoire of similar, yet distinct HBGA carbohydrate receptors available on mucosal surfaces that could interface with the remodeled architecture of the capsid ligand-binding pocket. The continuing evolution of new replacement strains suggests that, as with influenza viruses, vaccines could be targeted that protect against norovirus infections, and that continued epidemiologic surveillance and reformulations of norovirus vaccines will be essential in the control of future outbreaks.

What do “Back-to-School" Computers Have in Common with Health Education and Health Protection?

How to increase immunization levels in communities is a recurrent problem associated with missed opportunities. As communities gear-up for Back to School, health educators may encourage people to update their child, adolescent, and adult immunizations. Human herd immunity can protect communities from spread of infection, and an analogy is presented with “herd immunity for personal computers.” Both computer and biological viruses spread faster when a large portion of the population is unprotected. Just as individuals should receive immunization shots to protect self and families; computer systems can be protected against nasty computer code by using current anti-virus programs to limit the spread of viruses, worms, and Trojan horses from one computer to another. How much more would individuals rather receive timely shots that help to preserve health? An ounce of prevention is worth a pound of cure.

Time Limitation and the Role of Research in the Worldwide Attempt To Eradicate Malaria

The U.S. Congress established an intense, time-limited, worldwide malaria eradication program in 1958 and assigned operational responsibility to the U.S. Agency for International Development (and its predecessors). When the program was terminated on schedule in 1963, approximately $400 million had been consumed and malaria prevalence had greatly been reduced. Transmission began to increase thereafter. The open-ended WHO global eradication effort began in 1955 ended in 1969 and consumed approximately $15 million during the 1958-1963 period of progress, mainly provided by the United States. Intensified anti-malaria interventions continued after Congress discontinued direct support. Although malariological research was discouraged during the period of time limitation, it was embraced as the conceptual basis for the open-ended period of intervention that followed. This effort saved many lives but expended our ability to intervene against future epidemics and reduced human herd immunity. To avoid the "great gamble" inherent in any ambitious intervention against this disease, future programs should be designed to seek incremental, local antimalaria gains.