Cjepiva protiv malarije: Hoće li nova tehnologija DNK cjepiva utjecati na budući tečaj?

Razvoj cjepiva protiv malarije bio je jedan od najvećih izazova pred znanošću. Mosquirix^TM , a vaccine against malaria has recently been approved by WHO. Although the efficacy of this vaccine is about 37%, yet this is great step forward as this is first time any anti-malaria vaccine has seen the day. Among the other anti-malaria vaccine candidates, the DNA vaccines using adenovirus as an expression vector, with possibility to provide for multiple malarial antigens seem to have great potential as the technology employed has recently proved its worthiness in the case of Oxford/AstraZeneca (ChAdOx1 nCoV-2019) vaccine against COVID-19.  

cjepiva protiv malarija pokazali su se izazovom zbog složene životne povijesti parazita koji pokazuje različite razvojne faze u domaćinu, ekspresiju velikog broja različitih proteina u različitim stadijima, zamršenu interakciju između biologije parazita i imuniteta domaćina, zajedno s nedostatak odgovarajućih resursa i nedostatak učinkovite globalne suradnje zbog prevalencije bolesti u uglavnom zemljama trećeg svijeta. 

However, a few attempts have been made to generate and develop an effective vaccine against this dreadful disease. All these have been classified as pre-erythrocytic cjepiva as they involve the sporozoite protein and targets the parasite before it enters the liver cells.  The first to develop was a radiation-attenuated Plasmodium falciparum sporozoitno (PfSPZ) cjepivo¹ koji bi pružio zaštitu od P. falciparum infekcija u malarija-naïve adults. This was developed by GSK and the Walter Reed Army Institute of Research (WRAIR) in the mid 1970s but did not see the light of the day as there was no significant vaccine efficacy shown. The recent Phase 2 trials that were conducted in 336 infants aged 5–12 months to determine the safety, tolerability, immunogenicity and efficacy of the PfSPZ Vaccine in infants in a high-transmission malarija setting in western Kenya (NCT02687373)², također je pokazao slične rezultate da, iako je postojao porast odgovora protutijela ovisno o dozi nakon 6 mjeseci u skupinama s najnižim i najvišim dozama, odgovori T stanica bili su neotkriveni u svim dozama. Zbog nepostojanja značajne učinkovitosti cjepiva, odlučeno je da se ovo cjepivo ne provodi u ovoj dobnoj skupini. 

Još jedno cjepivo koje su razvili GSK i WRAIR 1984. je RTS,S cjepivo, nazvano Mosquirix^TM koje cilja na protein sporozoita i prvo je cjepivo koje je prošlo ispitivanje faze 3³ i prvi koji se procjenjuje u programima rutinske imunizacije u endemskim područjima malarije. Rezultati ovog ispitivanja pokazuju da je među djecom u dobi od 5-17 mjeseci koja su primila 4 doze RTS,S cjepiva, učinkovitost protiv malarije bila 36% tijekom 4 godine praćenja. RTS,S sadrži R, koji se odnosi na središnju ponavljajuću regiju, jedan visoko konzervirani tandem ponavljajući tetrapeptid NANP, T se odnosi na epitope T-limfocita Th2R i Th3R. Kombinirani RT peptid je genetski spojen na N-terminal površinskog antigena hepatitisa B (HBsAg), "S" (površinska) regija. Ovaj RTS se zatim ko-ekspresira u stanicama kvasca kako bi se dobile čestice slične virusu koje prikazuju i protein sporozoita (R ponavljanje regije s T) i S na svojoj površini. Drugi dio "S" izražen je kao nekondenzirani HBsAg koji se spontano spaja s RTS komponentom, otuda i naziv RTS,S.  

Another vaccine that has been developed against malarija je DNA-Ad vaccine that uses human adenovirusa za ekspresiju proteina sporozoita i antigena (antigen apikalne membrane 1)⁴. The phase 2 trials have been completed on 82 participants in a Phase 1-2 non-randomized open label trial to assess the Safety, Immunogenicity, and Efficacy of this vaccine in Healthy Malarija-Naïve Adults in the US. The highest sterile immunity achieved against malarija following immunization with this adenovirus-based subunit vaccine was 27%.  

U drugoj studiji, ljudski adenovirus promijenjen je u adenovirus čimpanze, a drugi antigen, TRAP (ljepljivi protein povezan s trombospondinom) spojen je na protein sporozoita i antigen apikalne membrane kako bi se poboljšala zaštita⁵. Odgovor cjepiva u ovom cjepivu s tri antigenske podjedinice bio je 25% u usporedbi s -2% u cjepivu s dvije podjedinice u usporedbi.  

The above studies suggest that the use of DNA adenovirus based multi-subunit cjepiva may afford better protection (as mentioned above) and also as is the case in study shown with the recent Oxford/AstraZeneca ChAdOx1 nCoV-2019 vaccine against COVID-19 that uses genetically engineered adenovirus as a vector to express spike protein as antigen. This technology can be exploited to express multiple protein targets to target the malarial parasite before it infects the liver cells. The current approved WHO vaccine utilises a different technology. However, time will tell when we will get an effective malarial vaccine that can take care of the disease burden of the African and the South-Asian countries to allow the world to overcome this deadly disease. 

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Reference:

1. Clyde DF, Most H, McCarthy VC, Vanderberg JP. Imunizacija čovjeka protiv malarije falciparum izazvane sporozitom. Am J Med Sci. 1973; 266 (3): 169–77. Epub 1973/09/01. PubMed PMID: 4583408. DOI: https://doi.org/10.1097/00000441-197309000-00002 

2. Oneko, M., Steinhardt, LC, Yego, R. sur. Sigurnost, imunogenost i učinkovitost PfSPZ cjepiva protiv malarije u dojenčadi u zapadnoj Keniji: dvostruko slijepo, randomizirano, placebom kontrolirano ispitivanje faze 2. Nat Med 27, 1636-1645 (2021). https://doi.org/10.1038/s41591-021-01470-y 

3. Laurens M., 2019.  RTS,S/AS01 vaccine (Mosquirix™): an overview. Human cjepiva & Immunotherapeutics. Volume 16, 2020 – Issue 3. Published online: 22 Oct 2019. DOI: https://doi.org/10.1080/21645515.2019.1669415 

4. Chuang I., Sedegah M., et al 2013. DNA Prime/Adenovirus Boost Malaria Vaccine Encoding P. falciparum CSP i AMA1 izazivaju sterilnu zaštitu povezanu s imunitetom posredovanim stanicama. PLOS One. Objavljeno: 14. veljače 2013. DOI: https://doi.org/10.1371/journal.pone.0055571 

5. Sklar M., Maiolatesi, S., et al 2021. Tri-antigen Plasmodium falciparum DNA prime—Adenovirus boost malaria vaccine regimen is superior to a two-antigen regimen and protects against controlled human malaria infection in healthy malaria-naïve adults. PLOS One. Published: September 8, 2021. DOI: https://doi.org/10.1371/journal.pone.0256980 

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