In a recent study published on the bioRxiv* preprint server, researchers described a messenger ribonucleic acid (mRNA) lipid nanoparticle vaccine encoding four conserved mpox virus surface proteins that induced virus-specific immunity from mpox and obtained heterologous protection when challenged with lethal vaccine virus. .
Study: A monkeypox lipid and mRNA nanoparticle vaccine targeting virus binding, entry, and transmission boosts protection against lethal orthopoxviral challenge. Image credit: MIA Studio/Shutterstock
background
The global outbreak of smallpox in 2022 resulted in widespread infections in nearly 30 countries outside the endemic distribution of the mpox virus. This strain of mpox virus was different from those responsible for previous outbreaks because of its ability to transmit from human to human. The mpox virus belongs to the genus Orthopoxvirus, which also contains the etiological agent of smallpox: the variola virus.
Although the smallpox vaccine, which uses live attenuated modified vaccinia virus, has been effective against smallpox virus, breakthrough smallpox infections have been observed after the first and second doses of JYNNEOS, the vaccine based on the modified Ankara vaccine (MVA). Also, since smallpox vaccinations were discontinued in most countries after the disease was eradicated, only stockpiled vaccines were available, and challenges in manufacturing the vaccine added to the concern. Therefore, there is an urgent need for vaccines that elicit mpoxvirus-specific immune responses and possibly protect against other Orthopoxvirus infections.
About the study
In the present study, the researchers targeted a set of mpox virus surface proteins that are highly conserved in orthopoxviruses and can induce T helper (Th-1) type 1 cell-dependent immune responses in vivo. The selected immunogens included surface proteins from the two infectious forms of Orthopoxvirus: the extracellular enveloped virion and the intracellular mature virion. Mpox virus antigens involved in cell entry (M1 and A29) and transmission (A35 and B6), which share more than 94% similarity with vaccine virus antigens, were selected for the vaccine .
Of the four, M1 and A29 are found in the mature virion, and A35 and B6 are found in the enveloped virion. The mRNA encoding the four antigens was selected from the mpox virus clade II, which is responsible for the 2022 outbreak. The mRNA sequences were modified to include a signal peptide from a region of influenza hemagglutinin 1 (M1 and A29), an N-terminal transmembrane region of the influenza neuraminidase 2 region (A35) or a truncated cytoplasmic tail (B6).
The lipid nanoparticle consisted of four lipids: cholesterol, a novel ionizable lipid SM-102, PEG2000-DMG, and 1,2-distearoyl-snglycero-3-phosphocholine (DSPC). Expi293 suspension cells were used to assess the expression of the antigens encoded by the selected mRNAs. Lipid nanoparticles containing individual antigens or various combinations of the four antigens were injected intramuscularly twice into mouse models with an interval of three weeks. The control group of mice was injected with MVA vaccine following the same regimen. Serum samples from mice were analyzed by flow cytometry for neutralizing antibodies against mpox virus. Binding antibody titers were also analyzed.
The binding profiles of fragment (Fc) crystallizable receptor gamma (FcgR) and isotype-specific antibodies to mpox virus induced by the quadrivalent mRNA vaccine were determined and compared with those induced by the MVA In addition, the ability of mpox virus mRNAs to elicit cross-reactive antibodies against vaccinia virus orthologs was also tested. Serum samples from mouse models vaccinated with individual and combined mpox virus antigens were also tested for cross-reactive immune responses against vaccine virus orthologs. Immunized mice were also challenged intranasally with lethal doses of vaccine virus.
results
The results indicated that the mRNA-lipid nanoparticle vaccine elicited greater neutralizing and spread-inhibitory activity than MVA vaccine against mpox virus and vaccinia virus. The mRNA vaccine also induced a higher Th-1 biased humoral immune response with greater FcgR binding.
Messenger RNA-lipid nanoparticle vaccines with single antigens provided partial protection in mice challenged with lethal doses of vaccine virus. In contrast, mRNA vaccines with combinations of two or three antigens or all four antigens protected mice against weight loss and death during lethal vaccine virus challenge.
The cross-protection elicited by the multivalent mpox virus mRNA vaccine was markedly superior to the immune response induced by the homologous MVA vaccine. Even a fourth dose of the tetravalent mpox virus mRNA vaccine protected against weight loss during lethal vaccine virus challenge. Bi- and trivalent mRNA vaccines also conferred sterilizing immunity during vaccine virus challenge. The single M1 antigen mRNA vaccine protected against the mature virion form of vaccinia virus, and the B6 antigen mRNA vaccine prevented the spread of the enveloped virion form.
Conclusions
The results indicated that the mRNA lipid nanoparticle mpox vaccine with single antigens and combinations of four surface proteins confers broad immunity against orthopoxviruses, with bi-, tri-, and quadrivalent vaccines eliciting significantly Th-1 biased humoral immune responses higher against the vaccine virus than the MVA vaccine.
*Important news
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and therefore should not be considered conclusive, guide clinical practice/health-related behavior, or be treated as established information.
Journal reference:
- Alec W Freyn, Caroline Atyeo, Patricia L Earl, Jeffrey L Americo, Gwo-Yu Chuang, Harini Natarajan, Tiffany R Frey, Jason Gall, Juan I Moliva, Ruth Hunegnaw, Guha Asthagiri Arunkumar, Clinton Ogega, Arshan Nasir, Hamilton Bennett, Joshua Johnson, Michael A Durney, Guillaume Stewart-Jones, Jay W Hooper, Tonya Colpitts, Galit Alter, Nancy J Sullivan, Andrea Carfi and Bernard Moss. (2022). Monkeypox mRNA and Lipid Nanoparticle Vaccine Targeting Virus Binding, Entry, and Transmission Boosts Protection Against Lethal Orthopoxviral Challenge. bioRxiv. doi: