The Experts below are selected from a list of 435 Experts worldwide ranked by ideXlab platform
Florian Krammer - One of the best experts on this subject based on the ideXlab platform.
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from Original Antigenic Sin to the universal influenza virus vaccine
Trends in Immunology, 2018Co-Authors: Carole Henry, Florian Krammer, Anna Karin E Palm, Patrick C WilsonAbstract:Antibody responses are essential for protection against influenza virus infection. Humans are exposed to a multitude of influenza viruses throughout their lifetime and it is clear that immune history influences the magnitude and quality of the antibody response. The ‘Original Antigenic Sin’ concept refers to the impact of the first influenza virus variant encounter on lifelong immunity. Although this model has been challenged Since its discovery, past exposure, and likely one’s first exposure, clearly affects the epitopes targeted in subsequent responses. Understanding how previous exposure to influenza virus shapes antibody responses to vaccination and infection is critical, especially with the prospect of future pandemics and for the effective development of a universal influenza vaccine.
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analysis of anti influenza virus neuraminidase antibodies in children adults and the elderly by elisa and enzyme inhibition evidence for Original Antigenic Sin
Mbio, 2017Co-Authors: Madhusudan Rajendran, Raffael Nachbagauer, Megan E Ermler, Paul Bunduc, Fatima Amanat, Ruvim Izikson, Manon M J Cox, Peter Palese, Maryna C Eichelberger, Florian KrammerAbstract:Antibody responses to influenza virus hemagglutinin provide protection against infection and are well studied. Less is known about the human antibody responses to the second surface glycoprotein, neuraminidase. Here, we assessed human antibody reactivity to a panel of N1, N2, and influenza B virus neuraminidases in different age groups, including children, adults, and the elderly. USing enzyme-linked immunosorbent assays (ELISA), we determined the breadth, magnitude, and isotype distribution of neuraminidase antibody responses to historic, current, and avian strains, as well as to recent isolates to which these individuals have not been exposed. It appears that antibody levels against N1 neuraminidases were lower than those against N2 or B neuraminidases. The anti-neuraminidase antibody levels increased with age and were, in general, highest against strains that circulated during the childhood of the tested individuals, providing evidence for "Original Antigenic Sin." Titers measured by ELISA correlated well with titers measured by the neuraminidase inhibition assays. However, in the case of the 2009 pandemic H1N1 virus, we found evidence of interference from antibodies binding to the conserved stalk domain of the hemagglutinin. In conclusion, we found that antibodies against the neuraminidase differ in magnitude and breadth between subtypes and age groups in the human population. (This study has been registered at ClinicalTrials.gov under registration no. NCT00336453, NCT00539981, and NCT00395174.)IMPORTANCE Anti-neuraminidase antibodies can afford broad protection from influenza virus infection in animal models and humans. However, little is known about the breadth and magnitude of the anti-neuraminidase response in the human population. Here we assessed antibody levels of children, adults, and the elderly against a panel of N1, N2, and type B influenza virus neuraminidases. We demonstrated that antibody levels measured by ELISA correlate well with functional neuraminidase inhibition titers. This is an important finding Since ELISA is a simpler method than functional assays and can be implemented in high-throughput settings to analyze large numbers of samples. Furthermore, we showed that low titers of broadly cross-reactive antibodies against neuraminidase are prevalent in humans. By the use of an appropriate vaccination strategy, these titers could potentially be boosted to levels that might provide broad protection from influenza virus infection.
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Analysis of Anti-Influenza Virus Neuraminidase Antibodies in Children, Adults, and the Elderly by ELISA and Enzyme Inhibition: Evidence for Original Antigenic Sin
American Society for Microbiology, 2017Co-Authors: Madhusudan Rajendran, Raffael Nachbagauer, Megan E Ermler, Paul Bunduc, Fatima Amanat, Ruvim Izikson, Peter Palese, Maryna C Eichelberger, Manon Cox, Florian KrammerAbstract:Antibody responses to influenza virus hemagglutinin provide protection against infection and are well studied. Less is known about the human antibody responses to the second surface glycoprotein, neuraminidase. Here, we assessed human antibody reactivity to a panel of N1, N2, and influenza B virus neuraminidases in different age groups, including children, adults, and the elderly. USing enzyme-linked immunosorbent assays (ELISA), we determined the breadth, magnitude, and isotype distribution of neuraminidase antibody responses to historic, current, and avian strains, as well as to recent isolates to which these individuals have not been exposed. It appears that antibody levels against N1 neuraminidases were lower than those against N2 or B neuraminidases. The anti-neuraminidase antibody levels increased with age and were, in general, highest against strains that circulated during the childhood of the tested individuals, providing evidence for “Original Antigenic Sin.” Titers measured by ELISA correlated well with titers measured by the neuraminidase inhibition assays. However, in the case of the 2009 pandemic H1N1 virus, we found evidence of interference from antibodies binding to the conserved stalk domain of the hemagglutinin. In conclusion, we found that antibodies against the neuraminidase differ in magnitude and breadth between subtypes and age groups in the human population. (This study has been registered at ClinicalTrials.gov under registration no. NCT00336453, NCT00539981, and NCT00395174.
Jonathan A Mccullers - One of the best experts on this subject based on the ideXlab platform.
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does glycosylation as a modifier of Original Antigenic Sin explain the case age distribution and unusual toxicity in pandemic novel h1n1 influenza
BMC Infectious Diseases, 2010Co-Authors: Tom Reichert, Gerardo Chowell, Hiroshi Nishiura, Ronald A Christensen, Jonathan A MccullersAbstract:A pandemic novel H1N1 swine-origin influenza virus has emerged. Most recently the World Health Organization has announced that in a country-dependent fashion, up to 15% of cases may require hospitalization, often including respiratory support. It is now clear that healthy children and young adults are disproportionately affected, most unusually among those with severe respiratory disease without underlying conditions. One possible explanation for this case age distribution is the doctrine of Original Antigenic Sin, i.e., novel H1N1 may be Antigenically similar to H1N1 viruses that circulated at an earlier time. Persons whose first exposure to influenza viruses was to such similar viruses would be relatively immune. However, this principle is not sufficient to explain the graded susceptibility between ages 20 and 60, the reduced susceptibility in children below age 10, and the unusual toxicity observed. We collected case data from 11 countries, about 60% of all cases reported through mid-July 2009. We compared sequence data for the hemagglutinin of novel H1N1 with sequences of H1N1 viruses from 1918 to the present. We searched for sequence differences that imply loss of Antigenicity either directly through amino acid substitution or by the appearance of sites for potential glycosylation proximal to sites known to be Antigenic in humans. We also considered T-cell epitopes. In our composite, over 75% of confirmed cases of novel H1N1 occurred in persons ≤ 30 years old, with peak incidence in the age range 10-19 years. Less than 3% of cases occurred in persons over 65, with a gradation in incidence between ages 20 and 60 years. The sequence data indicates that novel H1N1 is most similar to H1N1 viruses that circulated before 1943. Novel H1N1 lacks glycosylation sites on the globular head of hemagglutinin (HA1) near Antigenic regions, a pattern shared with the 1918 pandemic strain and H1N1 viruses that circulated until the early 1940s. Later H1N1 viruses progressively added new glycosylation sites likely to shield Antigenic epitopes, while T-cell epitopes were relatively unchanged. In this evolutionary context, Original Antigenic Sin exposure should produce an immune response increaSingly mismatched to novel H1N1 in progressively younger persons. We suggest that it is this mismatch that produces both the gradation in susceptibility and the unusual toxicity. Several murine studies suggest specific cell types as a likely basis of the unusual toxicity. These studies also point to widely available pharmaceutical agents as plausible candidates for mitigating the toxic effects. The principle of Original Antigenic Sin modified by glycosylation appears to explain both the case age distribution and the unusual toxicity pattern of the novel H1N1 pandemic. In addition, it suggests pharmaceutical agents for immediate investigation for mitigation potential, and provides strategic guidance for the distribution of pandemic mitigation resources of all types.
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Does Glycosylation as a modifier of Original Antigenic Sin explain the case age distribution and unusual toxicity in pandemic novel H1N1 influenza?
BMC Infectious Diseases, 2010Co-Authors: Tom Reichert, Gerardo Chowell, Hiroshi Nishiura, Ronald A Christensen, Jonathan A MccullersAbstract:Background A pandemic novel H1N1 swine-origin influenza virus has emerged. Most recently the World Health Organization has announced that in a country-dependent fashion, up to 15% of cases may require hospitalization, often including respiratory support. It is now clear that healthy children and young adults are disproportionately affected, most unusually among those with severe respiratory disease without underlying conditions. One possible explanation for this case age distribution is the doctrine of Original Antigenic Sin, i.e., novel H1N1 may be Antigenically similar to H1N1 viruses that circulated at an earlier time. Persons whose first exposure to influenza viruses was to such similar viruses would be relatively immune. However, this principle is not sufficient to explain the graded susceptibility between ages 20 and 60, the reduced susceptibility in children below age 10, and the unusual toxicity observed. Methods We collected case data from 11 countries, about 60% of all cases reported through mid-July 2009. We compared sequence data for the hemagglutinin of novel H1N1 with sequences of H1N1 viruses from 1918 to the present. We searched for sequence differences that imply loss of Antigenicity either directly through amino acid substitution or by the appearance of sites for potential glycosylation proximal to sites known to be Antigenic in humans. We also considered T-cell epitopes. Results In our composite, over 75% of confirmed cases of novel H1N1 occurred in persons ≤ 30 years old, with peak incidence in the age range 10-19 years. Less than 3% of cases occurred in persons over 65, with a gradation in incidence between ages 20 and 60 years. The sequence data indicates that novel H1N1 is most similar to H1N1 viruses that circulated before 1943. Novel H1N1 lacks glycosylation sites on the globular head of hemagglutinin (HA1) near Antigenic regions, a pattern shared with the 1918 pandemic strain and H1N1 viruses that circulated until the early 1940s. Later H1N1 viruses progressively added new glycosylation sites likely to shield Antigenic epitopes, while T-cell epitopes were relatively unchanged. Conclusions In this evolutionary context, Original Antigenic Sin exposure should produce an immune response increaSingly mismatched to novel H1N1 in progressively younger persons. We suggest that it is this mismatch that produces both the gradation in susceptibility and the unusual toxicity. Several murine studies suggest specific cell types as a likely basis of the unusual toxicity. These studies also point to widely available pharmaceutical agents as plausible candidates for mitigating the toxic effects. The principle of Original Antigenic Sin modified by glycosylation appears to explain both the case age distribution and the unusual toxicity pattern of the novel H1N1 pandemic. In addition, it suggests pharmaceutical agents for immediate investigation for mitigation potential, and provides strategic guidance for the distribution of pandemic mitigation resources of all types.
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Does Glycosylation as a modifier of Original Antigenic Sin explain the case age distribution and unusual toxicity in pandemic novel H1N1 influenza?
'Springer Science and Business Media LLC', 2010Co-Authors: Ra Christensen, Jonathan A Mccullers, Chowell G, Reichert T, Nishiura HAbstract:Background: A pandemic novel H1N1 swine-origin influenza virus has emerged. Most recently the World Health Organization has announced that in a country-dependent fashion, up to 15% of cases may require hospitalization, often including respiratory support. It is now clear that healthy children and young adults are disproportionately affected, most unusually among those with severe respiratory disease without underlying conditions. One possible explanation for this case age distribution is the doctrine of Original Antigenic Sin, i.e., novel H1N1 may be Antigenically similar to H1N1 viruses that circulated at an earlier time. Persons whose first exposure to influenza viruses was to such similar viruses would be relatively immune. However, this principle is not sufficient to explain the graded susceptibility between ages 20 and 60, the reduced susceptibility in children below age 10, and the unusual toxicity observed.Methods: We collected case data from 11 countries, about 60% of all cases reported through mid-July 2009. We compared sequence data for the hemagglutinin of novel H1N1 with sequences of H1N1 viruses from 1918 to the present. We searched for sequence differences that imply loss of Antigenicity either directly through amino acid substitution or by the appearance of sites for potential glycosylation proximal to sites known to be Antigenic in humans. We also considered T-cell epitopes.Results: In our composite, over 75% of confirmed cases of novel H1N1 occurred in persons ≤ 30 years old, with peak incidence in the age range 10-19 years. Less than 3% of cases occurred in persons over 65, with a gradation in incidence between ages 20 and 60 years.The sequence data indicates that novel H1N1 is most similar to H1N1 viruses that circulated before 1943. Novel H1N1 lacks glycosylation sites on the globular head of hemagglutinin (HA1) near Antigenic regions, a pattern shared with the 1918 pandemic strain and H1N1 viruses that circulated until the early 1940s. Later H1N1 viruses progressively added new glycosylation sites likely to shield Antigenic epitopes, while T-cell epitopes were relatively unchanged.Conclusions: In this evolutionary context, Original Antigenic Sin exposure should produce an immune response increaSingly mismatched to novel H1N1 in progressively younger persons. We suggest that it is this mismatch that produces both the gradation in susceptibility and the unusual toxicity. Several murine studies suggest specific cell types as a likely basis of the unusual toxicity. These studies also point to widely available pharmaceutical agents as plausible candidates for mitigating the toxic effects. The principle of Original Antigenic Sin modified by glycosylation appears to explain both the case age distribution and the unusual toxicity pattern of the novel H1N1 pandemic. In addition, it suggests pharmaceutical agents for immediate investigation for mitigation potential, and provides strategic guidance for the distribution of pandemic mitigation resources of all types. © 2010 Reichert et al; licensee BioMed Central Ltd.published_or_final_versio
Raffael Nachbagauer - One of the best experts on this subject based on the ideXlab platform.
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analysis of anti influenza virus neuraminidase antibodies in children adults and the elderly by elisa and enzyme inhibition evidence for Original Antigenic Sin
Mbio, 2017Co-Authors: Madhusudan Rajendran, Raffael Nachbagauer, Megan E Ermler, Paul Bunduc, Fatima Amanat, Ruvim Izikson, Manon M J Cox, Peter Palese, Maryna C Eichelberger, Florian KrammerAbstract:Antibody responses to influenza virus hemagglutinin provide protection against infection and are well studied. Less is known about the human antibody responses to the second surface glycoprotein, neuraminidase. Here, we assessed human antibody reactivity to a panel of N1, N2, and influenza B virus neuraminidases in different age groups, including children, adults, and the elderly. USing enzyme-linked immunosorbent assays (ELISA), we determined the breadth, magnitude, and isotype distribution of neuraminidase antibody responses to historic, current, and avian strains, as well as to recent isolates to which these individuals have not been exposed. It appears that antibody levels against N1 neuraminidases were lower than those against N2 or B neuraminidases. The anti-neuraminidase antibody levels increased with age and were, in general, highest against strains that circulated during the childhood of the tested individuals, providing evidence for "Original Antigenic Sin." Titers measured by ELISA correlated well with titers measured by the neuraminidase inhibition assays. However, in the case of the 2009 pandemic H1N1 virus, we found evidence of interference from antibodies binding to the conserved stalk domain of the hemagglutinin. In conclusion, we found that antibodies against the neuraminidase differ in magnitude and breadth between subtypes and age groups in the human population. (This study has been registered at ClinicalTrials.gov under registration no. NCT00336453, NCT00539981, and NCT00395174.)IMPORTANCE Anti-neuraminidase antibodies can afford broad protection from influenza virus infection in animal models and humans. However, little is known about the breadth and magnitude of the anti-neuraminidase response in the human population. Here we assessed antibody levels of children, adults, and the elderly against a panel of N1, N2, and type B influenza virus neuraminidases. We demonstrated that antibody levels measured by ELISA correlate well with functional neuraminidase inhibition titers. This is an important finding Since ELISA is a simpler method than functional assays and can be implemented in high-throughput settings to analyze large numbers of samples. Furthermore, we showed that low titers of broadly cross-reactive antibodies against neuraminidase are prevalent in humans. By the use of an appropriate vaccination strategy, these titers could potentially be boosted to levels that might provide broad protection from influenza virus infection.
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defining the antibody cross reactome directed against the influenza virus surface glycoproteins
Nature Immunology, 2017Co-Authors: Raffael Nachbagauer, Angela Choi, Ariana Hirsh, Irina Margine, Sayaka Iida, Aldo Barrera, Marcela Ferres, Randy A Albrecht, Adolfo Garciasastre, Nicole M BouvierAbstract:Infection with influenza virus induces antibodies to the viral surface glycoproteins hemagglutinin and neuraminidase, and these responses can be broadly protective. To assess the breadth and magnitude of antibody responses, we sequentially infected mice, guinea pigs and ferrets with divergent H1N1 or H3N2 subtypes of influenza virus. We measured antibody responses by ELISA of an extensive panel of recombinant glycoproteins representing the viral diversity in nature. Guinea pigs developed high titers of broadly cross-reactive antibodies; mice and ferrets exhibited narrower humoral responses. Then, we compared antibody responses after infection of humans with influenza virus H1N1 or H3N2 and found markedly broad responses and cogent evidence for 'Original Antigenic Sin'. This work will inform the design of universal vaccines against influenza virus and can guide pandemic-preparedness efforts directed against emerging influenza viruses.
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Analysis of Anti-Influenza Virus Neuraminidase Antibodies in Children, Adults, and the Elderly by ELISA and Enzyme Inhibition: Evidence for Original Antigenic Sin
American Society for Microbiology, 2017Co-Authors: Madhusudan Rajendran, Raffael Nachbagauer, Megan E Ermler, Paul Bunduc, Fatima Amanat, Ruvim Izikson, Peter Palese, Maryna C Eichelberger, Manon Cox, Florian KrammerAbstract:Antibody responses to influenza virus hemagglutinin provide protection against infection and are well studied. Less is known about the human antibody responses to the second surface glycoprotein, neuraminidase. Here, we assessed human antibody reactivity to a panel of N1, N2, and influenza B virus neuraminidases in different age groups, including children, adults, and the elderly. USing enzyme-linked immunosorbent assays (ELISA), we determined the breadth, magnitude, and isotype distribution of neuraminidase antibody responses to historic, current, and avian strains, as well as to recent isolates to which these individuals have not been exposed. It appears that antibody levels against N1 neuraminidases were lower than those against N2 or B neuraminidases. The anti-neuraminidase antibody levels increased with age and were, in general, highest against strains that circulated during the childhood of the tested individuals, providing evidence for “Original Antigenic Sin.” Titers measured by ELISA correlated well with titers measured by the neuraminidase inhibition assays. However, in the case of the 2009 pandemic H1N1 virus, we found evidence of interference from antibodies binding to the conserved stalk domain of the hemagglutinin. In conclusion, we found that antibodies against the neuraminidase differ in magnitude and breadth between subtypes and age groups in the human population. (This study has been registered at ClinicalTrials.gov under registration no. NCT00336453, NCT00539981, and NCT00395174.
Joshy Jacob - One of the best experts on this subject based on the ideXlab platform.
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strategies to alleviate Original Antigenic Sin responses to influenza viruses
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Jin Hyang Kim, William G Davis, Suryaprakash Sambhara, Joshy JacobAbstract:Original Antigenic Sin is a phenomenon wherein sequential exposure to closely related influenza virus variants reduces antibody (Ab) response to novel Antigenic determinants in the second strain and, consequently, impairs the development of immune memory. This could pose a risk to the development of immune memory in persons previously infected with or vaccinated against influenza. Here, we explored strategies to overcome Original Antigenic Sin responses in mice sequentially exposed to two closely related hemagglutinin 1 neuraminidase 1 (H1N1) influenza strains A/PR/8/34 and A/FM/1/47. We found that dendritic cell–activating adjuvants [Bordetella pertussis toxin (PT) or CpG ODN or a squalene-based oil-in-water nanoemulsion (NE)], upon administration during the second viral exposure, completely protected mice from a lethal challenge and enhanced neutralizing-Ab titers against the second virus. Interestingly, PT and NE adjuvants when administered during the first immunization even prevented Original Antigenic Sin in subsequent immunization without any adjuvants. As an alternative to uSing adjuvants, we also found that repeated immunization with the second viral strain relieved the effects of Original Antigenic Sin. Taken together, our studies provide at least three ways of overcoming Original Antigenic Sin.
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investigating Original Antigenic Sin responses to h5n1 influenza viruses
Journal of Immunology, 2010Co-Authors: Feda Masseoud, Ioanna Skountzou, Nigel J Temperton, Joshy JacobAbstract:H5N1 influenza A virus remains a global threat Since its outbreak in 1997. Its re-emergence in 2003 spread from Asia to Europe, the Middle-East and Africa, raiSing concerns of a possible pandemic. While stockpiling of H5N1 prepandemic vaccines has been initiated, strain prediction is difficult due to the emergence of distinct clades/subclades. Antigenic variation between vaccine and pandemic strains may confer cross-protection or result in Antigenic Sin, in which the immune response is directed against the Original strain rather than the novel protective Antigenic determinants. Observed between strains that have undergone Antigenic drift, this misdirected response may compromise protective immunity. This study was carried out to determine the extent to which Antigenic Sin interferes with immune responses to the potentially pandemic influenza H5 subtype. We immunized mice with a DNA vaccine encoding the full length HA from influenza A/Vietnam/1194 followed by a vaccine encoding HA of drifted H5N1 strains, ranging in genetic identity from 100%- 88%. We are currently assesSing responses directed against either the primary or the drifted strain by microneutralization uSing a pseudotyped lentivirus bearing HA from the respective H5N1 strains. By examining Antigenic Sin due to H5N1 viruses, we can better understand the behavior of the virus as it circulates in the human population, and therefore improve preparedness in the context of H5N1 vaccine development and pandemic planning.
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Original Antigenic Sin responses to influenza viruses
Journal of Immunology, 2009Co-Authors: Jin Hyang Kim, Ioanna Skountzou, Richard W Compans, Joshy JacobAbstract:Most immune responses follow Burnet's rule in that Ag recruits specific lymphocytes from a large repertoire and induces them to proliferate and differentiate into effector cells. However, the phenomenon of “Original Antigenic Sin” stands out as a paradox to Burnet's rule of B cell engagement. Humans, upon infection with a novel influenza strain, produce Abs against older viral strains at the expense of responses to novel, protective Antigenic determinants. This exacerbates the severity of the current infection. This blind spot of the immune system and the redirection of responses to the “Original Ag” rather than to novel epitopes were described fifty years ago. Recent reports have questioned the existence of this phenomenon. Hence, we revisited this issue to determine the extent to which Original Antigenic Sin is induced by variant influenza viruses. USing two related strains of influenza A virus, we show that Original Antigenic Sin leads to a significant decrease in development of protective immunity and recall responses to the second virus. In addition, we show that sequential infection of mice with two live influenza virus strains leads to almost exclusive Ab responses to the first viral strain, suggesting that Original Antigenic Sin could be a potential strategy by which variant influenza viruses subvert the immune system.
Alan L Rothman - One of the best experts on this subject based on the ideXlab platform.
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immunity to dengue virus a tale of Original Antigenic Sin and tropical cytokine storms
Nature Reviews Immunology, 2011Co-Authors: Alan L RothmanAbstract:Dengue is a mosquito-borne viral disease of expanding geographical range and incidence. The existence of four viral serotypes and the association of prior dengue virus infection with an increased risk for more severe disease have presented significant obstacles to vaccine development. An increased understanding of the adaptive immune response to natural dengue virus infection and candidate dengue vaccines has helped to define the specific antibody and T cell responses that are associated with either protective or pathological immunity during dengue infection. Further characterization of immunological correlates of disease outcome and the validation of these findings in vaccine trials will be invaluable for developing effective dengue vaccines.
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immunity to dengue virus a tale of Original Antigenic Sin and tropical cytokine storms
Nature Reviews Immunology, 2011Co-Authors: Alan L RothmanAbstract:Alan Rothman describes the types of immune response that are associated with protection and pathology during dengue virus infection. Although virus-specific antibodies provide protective neutralizing immunity, they can also facilitate infection of other host cells; the author discusses the implications of this for vaccine development.
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understanding the contribution of cellular immunity to dengue disease pathogenesis
Immunological Reviews, 2008Co-Authors: Anuja Mathew, Alan L RothmanAbstract:Abstract Dengue viruses (DENV) are the mosquito-borne viruses of greatest global public health importance. DENV circulate as four serotypes with significant immunologic cross-reactivity that does not provide protection from secondary infection with heterologous serotypes. The strong association of severe dengue illness, dengue hemorrhagic fever (DHF), with heterologous secondary infection and high cytokine levels has led to a prevailing view that DHF is immunologically mediated. In vitro studies of DENV-specific T lymphocytes, clinical studies of acute DENV infection, and immunologic studies in mouse models have provided evidence that in heterologous secondary DENV infection, there is preferential activation of memory T lymphocytes with lower avidity for the infecting virus ('Original Antigenic Sin') resulting in altered T-cell functional responses. In the setting of host genetic predisposition and high level viremia, with resulting high Antigenic burden, we postulate that a skewed T-cell cytokine response leads to plasma leakage in DHF. A better understanding of the immune responses associated with increased or decreased risk for DHF will be of immense value for the clinical studies of candidate multivalent DENV vaccines anticipated to take place in the next several years.