11 May 2023 Episode 333 Dengue and vaccination

Thu, 05/11/2023 - 17:39

Episode 333: Dengue and vaccination

Dear colleagues,

After “the rise and fall” of Dengvaxia (from Sanofi-Pasteur), there is now a new promising vaccine: Qdenga (from Takeda). What to think about it?

Ep 333-1: In a recent advice (April 23) of the Belgian Super Health Council (BSHC) states the following:

… (Dengvaxia®) is licensed by the European Medicines Agency only for people aged 6–45 years with test-confirmed previous dengue infection. However, Dengvaxia® is not commercialised for use in Belgium.

On December 8, 2022 the European Commission (EC) granted marketing authorization for dengue vaccine Qdenga® (Dengue Tetravalent Vaccine [Live, Attenuated]) (TAK-003) for the prevention of dengue disease in individuals from four years of age in the European Union (EU). Qdenga® is on the Belgian market since March 2023.

… the Superior Health Council (SHC) recommends vaccination against Dengue with Qdenga® for people residing for a period of more than 4 weeks, long-term travelers (> 4 weeks) or frequent travelers from four years of age meeting all 3 of the following criteria:

1. Having had dengue before (based on history or laboratory confirmed3);

2. Travelling to a dengue endemic region, cfr. Map https://www.healthmap.org/dengue/en/;

3. Receiving both priming doses before departure.

Considering the many uncertainties about favourable and unfavourable effects of the vaccine, it is important to discuss the expected benefits and secondary effects of the vaccine with the travellers.

In this episode, I will first repeat some basic info on Dengue in Par 1. Based on that background, I will then discuss the pros and cons of both vaccines in more detail in Par 2, in order to provide you with the data to understand the advice of the BSHC and evaluate the usefulness of Dengue vaccination.

See

Par 1 Basics on Dengue Several pictures from Ep 333-2 = a slide presentation for a master course

1.2. VIROLOGY

Ep 333-3: Niyati Khetarpal J Imm Res 2016: Review

Genome organization and membrane topology of dengue virus

The viral RNA is translated as a single polyprotein consisting of structural (light brown-C, prM, and E) and nonstructural (dark brown-NS1, 2A, 2B, 3, 4A, 4B, and 5) protein components. Symbols C, prM, E, NS, and PM denote capsid protein, precursor membrane protein, envelope protein, nonstructural proteins, and plasma membrane, respectively.

This single polyprotein then gets processed by viral (green arrow) and host (black arrow) proteases.The structural proteins (prM and E) remain anchored on the luminal side of the Endoplasmic Reticulum membrane. The C protein is anchored on the cytoplasmic side of ER membrane.

prM is later cleaved by furin (red arrow) in the Trans- Golgi into the pr peptide and M protein.

The NS proteins are mainly processed by NS2B-NS3 (viral protease) in the cytoplasm. NS2A/2B and NS4A/4B are transmembrane proteins and thus stay anchored in the ER.

The approximate molecular weight (in kDa) of each protein has been indicated in braces.

Organization of E protein on dengue virus surface during its life cycle.

(a) The E protein is colored as follows: EDI (red), EDII (yellow), EDIII (blue), and the FL (green). prM and M protein are colored as cyan. (a) Immature virus contains 60 trimeric spikes of E and prM heterodimer.

(b) Mature virus contains 90 homodimers of E protein.

(c) These homodimers then further undergo reorganization to form fusion active E homotrimers in which fusion loop is exposed. M protein is not shown in the fusion trimer for simplicity.

E, C, M, FL, and prM denote envelope, capsid, membrane, fusion loop, and precursor membrane, respectively.

1.2 CLINICAL MANIFESTATIONS

Ep 333-4: CDC Pathophysiology of severe Dengue

Occurs among infants and patients with secondary dengue virus (DENV) infections (i.e., infection with a different DENV serotype from what they were previously infected with earlier in life).

Widely-cited hypothesis for this occurrence is antibody-dependent enhancement (ADE) of disease. ADE occurs when non-neutralizing anti-DENV antibodies bind to but do not neutralize an infecting DENV. This virus-antibody complex allows for enhanced viral entry into host cells, specifically dendritic cells and macrophages. Once inside the cell, the virus replicates and generates higher virus titers in the blood than when anti-DENV antibody is not present, which results in a “cytokine storm” and ultimately leading to more severe disease.

1.3. EPIDEMIOLOGY: 400,000,000 cases each year with 20,000 deaths

Ep 333-5: Maria Guzman Lancet Geographical distribution

Ep 333-6: Bhatt Nature 2023: Global risk (b) and burden as a proportion of population (c) in 2010

Clearly, South- and South-East Asia are most affected areas

1.4. SEROTYPES

Spread of serotypes over the world between 1974 (a) and 2004 (b)

Ep 333-7: Congcong Goa Global serotype distribution up to 2015

Globally, after 2010 DENV-1 dominated the mono-infection outbreaks (17/34, 50.0%)

Coinfection with all four serotypes continued to dominate the coinfection outbreaks (17/46, 37.0%).

Regional differences:

South-East Asia: co-infections with all 4 serotypes
DENV-1 was most common in the European region;
DENV-1 and DENV-2 were most common in the African region and American region;
DENV-2 and DENV-3 were most frequently observed in the Eastern Mediterranean region

Mortality according to serotype: DENV-2 = 2 % > DENV 3 = 1.6 % > DENV-4 = 0.7 % > DENV-1 = 0.3 %

1.5. IMMUNO-PATHOLOGY

Par 2 VACCINES

2.1. Dengvaxia or CYD-TDV: Three doses (0.5 mL each) 6 months apart (at month 0, 6, and 12)

Ep 333-8: Hadinegoro NEJM 2015 Efficacy and safety of Dengvaxia during first 25 months in endemic Asian-Pacific (= CYD-14 trial) and Latin-American (CYD-15) countries.

Overview of the Surveillance Phase and Long-Term Follow-up Phase of the CYD-TDV Candidate Vaccine Trials

CYD-TDV is a candidate recombinant, live, attenuated, tetravalent dengue vaccine that has been assessed in two phase 3 randomized

efficacy studies (called CYD14 and CYD15) involving a total of more than 31,000 participants between the ages of 2 and 16 years in

Asian–Pacific and Latin American countries. In addition, 3203 of 4002 participants (80%) who were between the ages of 4 and 11 at initial

enrollment in the phase 2b CYD23 trial in Thailand are being followed in the CYD57 trial. The trials had similar designs. According to

the study designs, the long-term follow-up phase will continue for a total of 6 years after enrollment.

Clearly, a warning signal that the unequal effect according to serotype and the low efficacy in seronegative children could be a problem

Ep 333-9: Shridhar NEJM 2018: 5 years follow-up after vaccinationconfirms the problem

In persons with previous exposure (sero-positive): CYD-TDV protected against severe virologically confirmed dengue (VCD) and hospitalization for VCD
In non-exposed (seronegative) persons there was a higher risk of severe VCD and hospitalization

(this was observed in all age groups of children 2-16 years old)

MI (multiple input); TMLE (targeted minimum loss based estimation; NS1 = anti-non-structural protein 1) = different assessing serostatus

Conclusion: clear effect of “enhancement” of risk on severe dengue in seronegative children

2.2. QDengva or TAK-003: 2doses 3 months apart.

Ep 333-9: Shibadas Biswal NEJM 2019 vol 381: Safety and efficacy of Takeda-003 (Qdenga in children and adolescents in Asia and Latin -America during 18 months.

Slightly lower overall efficacy in seronegative subjects, but similar protection against hospitalization
Slightly lower overall protection in youngest children (4-5 years)
More effective against DENV-2 ( = opposite of Dengvaxia)
Highly effective against hospitalization and Dengue hemorrhagic fever

Seronegative children have slightly higher chance on virologically confirmed dengue and hospitalization in placebo group, but vaccine efficiently inhibits those events.

Ep 333-11: Luis Rivera CID 2022: Three years efficacy and safety of TAK-003

High but declining efficacy against virally confirmed Dengue (VCD), lowest in children 4-5 years
Sustained high efficacy against hospitalization, but slightly lower in seronegatives

Highest titers against DENV-2 (as expected)

Evolution of virally confirmed Dengue and of Dengue hospitalizations

Clear tendency of rising cases during third year → booster needed !?

Ep 333-12: Gabriela Paz-Bailey Feb 23: ACIP Working Group on Takeda-003

Results after 57 months (= 4 years 9 months) summarized from all RCT

Ep 333-13: Smriti Mallapaty Nature 9 Nov 2022: Dengue vaccine poised for roll-out but safety concerns linger

Indonesia has decided to roll-out without restrictions for individuals between 6 and 45 years old and EMA has approved, despite the doubts about effectiveness or even ADE effects for DENV-3 and DENV-4 in seronepatives

Indonesia: Enormous burden:

Dropping testing for past dengue exposure makes the vaccine more practical and easier to roll out
By age of six already half of the children are seropositive

EMA: DENV-1 and DENV-2 are responsible for most of the dengue burden globally, and efficacy against those serotypes “outweights any remaining uncertainty on lack of efficacy”, against DENV-3 and DENV-4.

In the Belgian guidelines, seropositivity remains a requirement.

GENERAL CONCLUSIONS

Serotype-specific enhancement, leading to severe disease and mortality is a “wicked problem” in Dengue infection, especially in children, pregnant women and other vulnerable persons. We know now that it can also be triggered by primary vaccination with Dengvaxia in previously unexposed children.

Qdenga clearly is a more potent vaccine. Throughout the 4.5 years follow-up, it remains effective against infection and more so against hospitalization by all serotypes in previously seropositive children.

Conversely, in seronegative children, after 4 years, it is still highly active against DENV-2 and also against DENV-1, but not against DENV-3 and DENV-4. Fortunately, even in vaccinated seronegatives there is no clear evidence of enhancement by DENV-3/4 until now. But that was also the case in the mid-term (25 weeks) follow-up of Dengvaxia and it changed in the wrong direction lateron.

Future studies will elucidate whether a booster of Qdenga could re-install potent protection and prevent any tendency to enhancement. Obviously, as a follow-up of the recent successes in COVID and RSV, new Dengue vaccines, based on adjuvanted protein or mRNA may emerge,.

Important remark: This clear-cut enhancement of Dengue disease after previous infection or Dengvaxia vaccination is to be distinguished from what has been observed and suggested in Influenza and SARS-CoV-2. In those cases, infection or vaccination with a particular variant also results in “imprinting” or “original antigenic sin”, meaning that the immune system is “skewed” to the epitopes of the previous variant and unable to mount a very potent response to some new “escape” variants. As a consequence, protection to infection with the new “escape” variant will be weak or even absent (with a minority body of data even suggesting slight enhancement of infection risk). However, vaccination may still be able to prevent severe disease, based on humoral (= antibody), but also T cell responses towards more conserved epitopes.

What is the reason for this (fortunate) discrepancy?

The high susceptibility of dendritic cells, monocytes and macrophages to Dengue virus infection is thought to be important for enhancement: those cells express high numbers of Fc receptors and therefore “enhancing antibodies” could dramatically increase their viral infection/production and ensuing inflammatory reactions.

With regard to Influenza and SARS-CoV-2, myeloid mononuclear cells seem less susceptible to these viruses, which could explain the absence of clinically relevant enhancement via antibodies.

It should be recognized, however, that this is an hypothesis, as we do not know what the exact mechanism is of enhancement in Dengue e.g. whether it is purely antibody-based or whether NK cells, T cells or other components of the immune system also play a role.

To be continued….

Best wishes

Guido