immune response to the current strain, leading paradoxically to more virus entry and uptake. immune system interaction in recent years, many studies have shown that flaviviruses, especially dengue virus, has the ability to inhibit the innate immune response during the infection. indeed, dengue virus has many nonstructural proteins that allow the inhibition of various mediators of the innate immune system response. these proteins act on two levels : inhibition of interferon signaling by blocking signal transducer ns4b is a small, hydrophobic protein located in association with the endoplasmic reticulum. it may block the phosphorylation of stat 1 after induction by interferons type i alpha & beta. in fact, as the activity of tyk2 kinase decreases in association with dengue virus, so too does stat 1 phosphorylation. furthermore, the innate immune system's response to the virus is further damped as expression of interferon-stimulating gene(s) (isg) is restricted by the aforementioned 'ns4b' protein. ns2a and ns4a cofactor may also take part in the stat 1 inhibition. ns5 - the presence of this 105-kda protein results in inactivation of stat2 (via the signal transduction of the response to interferon) when it is expressed alone. when ns5 is cleaved with ns4b by a protease (ns2b3), it can degrade stat2. in fact, after the cleavage of ns5 by the protease, an e3 ligase association with stat2 occurs, and the e3 ligase targets stat2 for the degradation. inhibition of the type i interferon response ns2b3-b protease complex is a proteolytic core consisting of the last 40 amino acids of ns2b and the first 180 amino acids of ns3. cleavage of the ns2b3 precursor activates the protease complex. this protease complex allows the inhibition of the production of type i interferon by reducing the activity of ifn-beta promoter; ns2b3 protease complex is involved in inhibiting the phosphorylation of irf3. the ns2b3 protease complex inhibits (by cleaving) protein mita which allows the irf3 activation. mosquito d7 saliva protein dengue virus is transmitted by the mosquito species aedes aegypti, which produces saliva that contains over 100 unique proteins, including the protein family d7. scientists used to believe that a. aegypti saliva, when being transmitted, actually enhanced dengue virus in the body. the mosquito's saliva was thought to make the virus spread faster due to the weakened immune response of its host. however, a current study has found that the protein d7 hinders the virus transmission into the host cells. the immune responses of antibodies that are trying to fight off the foreign virus actually increase transmission and make the infection worse. levels of protein d7 are more prevalent in salivary glands of dengue-infected mosquitoes compared to those uninfected ones. d7 is found in mosquito saliva and was thought to assist the process of blood feeding. despite the prior assumptions, d7 can modulate the host cell and act against the virus to prevent viral infection. unfortunately, d7 proteins provoke immune responses, which raise anti-d7 antibody levels. these antibodies inhibit the function of d7 proteins, which enhance transmission of dengue virus. although immune responses against d7 proteins might impair their antiviral activity, a study showed that non-denv subjects have slightly higher anti-d7 igg levels than infected ones, although it was not statistically significant. thus, more studies over d7 protein family are needed do elucidate its role on denv infection and its applicability in medicine. vaccine research main article: dengue vaccine only one vaccine for dengue is currently approved in 11 countries (mexico, the philippines, indonesia, brazil, el salvador, costa rica, paraguay, guatemala, peru, thailand, and singapore). several vaccines are under development by private and public researchers. developing a vaccine against the disease is challenging. with four different serotypes of the virus that can cause the disease, the vaccine must immunize against all four types to be effective. vaccination against only one serotype could possibly lead to severe dengue hemorrhagic shock when infected with another serotype due to antibody-dependent enhancement. when infected with dengue virus, the immune system produces cross-reactive antibodies that provide immunity to that particular serotype. however, these antibodies are incapable of neutralizing other serotypes upon reinfection and actually increase viral replication. when macrophages consume the 'neutralized' virus, the virus is able to replicate within the macrophage, causing disease. these cross-reactive, ineffective antibodies ease access of virus into macrophages, which induces more severe disease (dengue hemorrhagic fever, dengue shock syndrome). a common problem faced in dengue-endemic regions is when mothers become infected with dengue; after giving birth, offspring carry the immunity from their mother and are susceptible to hemorrhagic fever if infected with any of the other three serotypes. one vaccine was in phase iii trials in 2012 and planning for vaccine usage and effectiveness surveillance had started. in 2009, sanofi-pasteur started building a new facility in neuville-sur-saône' (fr), a suburb of lyon (france). this unit produces four-serotype vaccine for phase iii trials. in september 2014, the sanofi-pasteur ceo gave early results of the phase iii trial efficacy study in latin america. the efficacy per serotype (st) varied widely, 42.3% for st2, 50.3% for st1, 74.0% for st3, and 77.7% for st4. the full analysis of data from the phase iii latin american-caribbean study will be reviewed by external experts before being published in a peer-reviewed scientific journal. primary results has to be presented at the american society of tropical medicine and hygiene annual meeting, held november 2–6, 2014, in new orleans. in september 2012, one of the vaccines was reported to not have done well in clinical trials. in late 2015 and early 2016, the first dengue vaccine, dengvaxia (cyd-tdv) by sanofi-pasteur, was registered in several countries for use in individuals 9–45 years of age living in endemic areas. on may 1, 2019, the u.s. food and drug administration announced the approval of dengvaxia, the first vaccine for the prevention of dengue disease caused by all dengue virus serotypes in people ages 9 through 16 who have laboratory-confirmed previous dengue infection and who live in endemic areas. dengue is endemic in the u.s. territories of american samoa, guam, puerto rico, and the u.s. virgin islands. drug research there are no approved direct antiviral treatments for dengue fever. most antiviral drug research for dengue infections has focussed on inhibition of the ns2b/ns3 protease or ns5 proteins. reported protease inhibitor approaches have focussed mainly on targeted covalent inhibitors. one drug, balapiravir, a repurposed hepatitis c ns5 polymerase inhibitor progressed to a phase ii clinical trial before being stopped due to lack of efficacy.