news & views

clinical use of these drugs in the future

Indolent systemic mastocytosis Advanced systemic mastocytosis
in select populations of patients with
Avapritinib
indolent disease.
Complement C3a, C5a
Overall, data from the EXPLORER and
KIT PATHFINDER studies strongly support
MRGPRX2
(D816V)
Liver: Spleen: avapritinib as a first-line treatment option
hepatomegaly,
ascites, portal
splenomegaly,
hypersplenism
in patients with advanced SM, with the
IgG IgE hypertension
GI:
exception of those with thrombocytopenia
Tryptase Bone marrow: malabsorption, and those with substantial baseline cognitive
Heparin weight loss
PAF Bradykinin
severe anemia,
neutropenia,
impairments. Future trials may focus on the
Histamine
Leukotrienes, prostaglandins thrombocytopenia role of KIT D816V–selective inhibitors as
IL-6, TNF
Skeletal:
Skin:
urticaria pigmentosa
part of combination regimens with other
osteopenia,osteoporosis,
pathological fractures
(also present in cytoreductive approaches in patients with
indolent disease)
Flushing, hives,
angioedema
Hypotension,
syncope
Abdominal cramping,
nausea, diarrhea,
high-risk advanced SM. ❐
brain fog

Mariana Castells1,2 ✉ and Cem Akin3

Fig. 1 | SM symptoms, mediators and organ impact of indolent and advanced disease. MRGPRX2, G
1
Division of Allergy and Clinical Immunology,
protein–coupled receptor; IgG and IgE, immunoglobulins; PAF, platelet-activating factor; IL-6, Brigham and Women’s Hospital, Boston, MA,
interleukin 6; TNF, tumor-necrosis factor; GI, gastrointestinal. USA. 2Department of Medicine, Harvard Medical
School, Boston, MA, USA. 3Division of Allergy and
Immunology, Department of Internal Medicine,
University of Michigan, Ann Arbor, MI, USA.
before this exclusion. Other side effects in The use of avapritinib should be ✉e-mail: [email protected]
PATHFINDER included cognitive adverse guided by a proactive monitoring
events, which occurred in 11% of patients strategy to identify patients who develop Published online: 6 December 2021
and were generally mild. Interestingly, the thrombocytopenia and may be at risk for https://doi.org/10.1038/s41591-021-01588-z
cognitive domain in the EORTC-QLQ-C30 intracranial bleed, which will facilitate
quality-of-life scale improved overall, appropriate dose modifications or References
despite these adverse events; the discontinuation of the drug. The effect of 1. Valent, P., Akin, C. & Metcalfe, D. D. Blood 129, 1420–1427 (2017).
2. Metcalfe, D. D. J. Invest. Dermatol. 96, 2S–4S (1991).
mechanisms underlying these events are avapritinib in terms of symptom reduction 3. Castells, M. & Austen, K. F. Int. Arch. Allergy Immunol. 127,
yet to be elucidated. and decrease in skin lesions is encouraging 147–152 (2002).
Advanced SM is a complex and not only for patients with advanced SM 4. Theoharides, T. C., Valent, P. & Akin, C. N. Engl. J. Med. 373,
163–172 (2015).
heterogeneous disease often associated but also for those with indolent SM, 5. Escribano, L., Akin, C., Castells, M., Orfao, A. & Metcalfe, D. D.
with other myeloproliferative neoplasms who typically carry only the KIT D816V Ann. Hematol. 81, 677–690 (2002).
and other mutations, in addition to the KIT mutation and may be more amenable 6. Escribano, L. et al. J. Allergy Clin. Immunol. 124, 514–521 (2009).
7. Lim, K. H. et al. Blood 113, 5727–5736 (2009).
D816V mutation. Both the EXPLORER to therapies that specifically target this 8. Nagata, H. et al. Proc. Natl Acad. Sci. USA 92, 10560–10564 (1995).
trial and the PATHFINDER trial excluded variant12,13. Preliminary results from an 9. DeAngelo, D. J. et al. Nat. Med. https://doi.org/10.1038/s41591-
patients with acute myeloid leukemia or ongoing study using avapritinib in low 021-01538-9 (2021).
10. Gotlib, J. et al. Nat. Med. https://doi.org/10.1038/s41591-021-
very-high-risk myelodysplastic syndrome, doses in patients with indolent SM yielded 01539-8 (2021).
as defined by the Revised International positive results in terms of both symptom 11. Gotlib, J. et al. N. Engl. J. Med. 374, 2530–2541 (2016).
Prognostic Scoring System. The optimal reduction and a decrease in markers of 12. Castells, M. & Butterfield, J. J. Allergy Clin. Immunol. Pract. 7,
treatment strategies for advanced SM mast-cell burden, with no serious adverse 1097–1106 (2019).
13. Akin et al. J. Allergy Clin. Immunol. 145, AB336 (2020).
associated with these poor prognostic events13. Treatment of symptomatic patients
factors remain to be determined, and with indolent SM concurrently with Competing interests
may be further guided by individual anti-mediator treatment (e.g., antihistamines M.C. and C.A. have consultancy agreement with and
mutational profiling. or mast-cell stabilizers) may expand the receive research funding from Blueprint Medicines.

INFECTIOUS DISEASE

mRNA vaccines offer hope for HIV

mRNA technology may be uniquely positioned to tackle a major hurdle for HIV vaccines: the elicitation of broadly
cross-reactive neutralizing antibodies. A preclinical study takes the first step toward this goal.

Lynn Morris

T
he remarkable success of mRNA Whether this unique technology platform immunodeficiency virus (HIV) is now under
vaccines against COVID-19 has can be used to tackle the more complex intense scrutiny. In this issue of Nature
been nothing short of miraculous. task of developing a vaccine against human Medicine, a preclinical study by Zhang et al.

2082 Nature Medicine | VOL 27 | December 2021 | 2078–2084 | www.nature.com/naturemedicine

 news & views

interestingly, to many other HIV epitopes

HIV-1 Env SARS-CoV-2 spike
— a considerable improvement on the
strain-specific ‘glycan-hole’ responses
seen with SOSIP proteins. It will be
important in future studies to isolate B
cells from mRNA-immunized animals
to ascertain whether they are capable of
broad neutralization and if they carry the
genetic features associated with known
bNAb lineages. Although the results from
CD4bs (blue) Zhang et al.1 are encouraging for the
V2 glycan (red)
V3 glycan (green) RBD (red)
HIV vaccine field, this is a complex and
Interface (yellow) NTD (cyan) impractical protocol that requires multiple
Glycans (orange) Glycans (orange)
immunizations with high doses of mRNA.
Moreover, the levels of bNAbs elicited in this
Fig. 1 | Complexity of HIV-1 Env versus SARS-CoV-2 spike. HIV Env (left) has multiple conformational study were extremely low and took a year to
bNAb epitopes (four of the six epitopes are shown here), is densely covered in glycans, and elicits a develop, and their role in protection from
polyclonal neutralizing antibody response. Genes encoding antibodies to Env are heavily mutated, and infection remains unclear.
bNAbs are rarely elicited by infection or vaccination. In contrast, the SARS-CoV-2 spike protein (right) is mRNA technology has only recently
lightly covered in glycans, and the receptor-binding domain (RBD) is the main immunodominant epitope, come of age; it was originally hampered by
with the N-terminal domain (NTD) targeted to a lesser extent. It generates a focused neutralizing instability and unfavorable immunogenicity,
antibody response; genes encoding antibodies to spike protein have limited or no mutations, and bNAbs but decades of research have solved these
are commonly elicited after infection and vaccination. CD4bs, CD4-binding site. Images from RCSB problems, and the advantages of mRNA
Protein Data Bank (https://www.rcsb.org/) accession codes 4ZMJ (glycans transposed from 5FUU; HIV as a vaccine platform continue to emerge5.
Env) and 6VSB (glycans transposed from 7CN9; SARS-CoV-2 spike protein). We thank T. Moyo-Gwete These include rapid development, ease of
for preparation of this figure. manufacture and scalability, which offer
advantages over the traditional vector-based
or protein-based vaccines being pursued in
the HIV field. For example, mRNA would
suggests that the mRNA platform may be up ‘SOSIP proteins’ induced only autologous enable testing of sequential immunization
to the challenge1. The authors encapsulated strain–specific neutralizing antibodies2. In and lineage-based approaches that require
mRNA encoding the HIV envelope the present study by Zhang et al., antibodies multiple immunogens with minor but
glycoprotein (Env) (the equivalent of the elicited by the Env–Gag mRNA were able important sequence changes6. mRNA is
SARS-CoV-2 spike protein), together with to neutralize almost all members of a global also considerably cheaper to produce and
the structural HIV group-specific antigen panel of HIV isolates, classified as having a can be modified as needed, an important
protein (Gag), in a lipid nanoparticle, tier 2 phenotype1. This represents a major consideration for rapidly mutating viruses
to produce virus-like particles (VLPs) step forward for a vaccine against HIV, as like HIV. Among the vaccines against
in vivo. These Env-expressing VLPs elicited this phenotype is typical of most circulating COVID-19, those based on the mRNA
broadly neutralizing antibodies (bNAbs) strains, which are difficult to neutralize due platform have superior immunogenicity
and other immune responses that were to a closed Env conformation. and stimulate both B cell responses and
protective against viral challenge in a It is likely that a number of factors T cell responses7,8. The precise mechanisms
macaque model. Although the VLPs were contributed to the greater immunogenicity underlying mRNA immunogenicity,
not nearly as immunogenic or as efficacious of the mRNA vaccine designed by Zhang however, are still unknown, and much
as mRNA vaccines against COVID-19, these et al.1. The endogenous expression of the remains to be learned if they are to be
results are encouraging and illuminate a native Env on the surface of a VLP would optimized and applied to HIV prevention.
pathway toward inducing the higher and preserve conformational epitopes, and Nonetheless, the vast amount of safety data
more-durable antibody responses needed to VLPs were also shown to contain double available from mRNA vaccines against
prevent infection with HIV. the number of Env molecules present in an COVID-19 will probably contribute to
This is no small feat; Env is a formidable HIV viral particle. Furthermore, mRNA streamlined regulatory approval processes
target that fails to induce the right kind of continues to be expressed for several days for vaccines against HIV and other diseases.
antibodies even in the majority of people after administration, providing ongoing In contrast to the swift success of
who are infected with HIV. Unlike spike immunostimulation3. Another potential vaccines against COVID-19, the story of the
protein, which is relatively stable and advantage is the ability of VLPs to bind to development of vaccines against HIV has
contains just a few immunodominant antigen-presenting cells, which guarantees been long and troubled. Of the eight vaccine
epitopes (mostly restricted to the delivery of mRNA into the appropriate efficacy trials conducted so far, only one (with
receptor-binding domain), Env is a complex cells and the induction of follicular a viral-vector and protein-based vaccine
trimeric protein with multiple dispersed helper T cells that are crucial for B cell prime–boost regimen) has shown moderate
antibody epitopes — many of which are development in germinal centers4. Zhang efficacy, although the follow-up trial failed to
conformational and heavily coated in sugars et al. also chose an HIV Env sequence that replicate this result9. This has shifted the field
that shield them from antibody attack (Fig. lacks a glycan at position 276; this enabled back to the pursuit of a vaccine able to induce
1). The ability to generate soluble trimeric better access to the B cell precursors of bNAbs. Recently, the Antibody-Mediated
Env proteins through the introduction bNAbs that target the CD4-binding site Prevention clinical trials demonstrated that a
of key mutations was a major advance in on the viral envelope1. Indeed, Env–Gag monoclonal bNAb against the CD4-binding
immunogen design, although these so-called mRNA elicited antibodies to that site and, site can prevent infection of humans with

Nature Medicine | VOL 27 | December 2021 | 2078–2084 | www.nature.com/naturemedicine 2083

news & views

HIV10, although it came with the sobering HIV to integrate into the human genome KwaZulu-Natal, Durban, South Africa.
realization that high levels of bNAbs will necessities that a vaccine elicits antibodies ✉e-mail: [email protected]
probably be required (P. Gilbert, personal able to block every viral particle. Whether
communication). Another approach to further optimization of Env immunogens, Published online: 9 December 2021
generating bNAbs is to trigger the B cell together with the strong priming effect of an https://doi.org/10.1038/s41591-021-01602-4
precursors of specific bNAb lineages. One mRNA vaccine platform, is able to achieve
References
such germline-targeting immunogen is this will require further investigation. The 1. Zhang. P. et al. Nat. Med. https://doi.org/10.1038/s41591-021-
eOD-GT8, a nanoparticle coated with HIV hope is that the lessons learned from the 01574-5 (2021).
Env gp120 proteins, which binds rare B cells development of vaccines against COVID-19 2. Sanders, R. W. et al. Science 349, aac4223 (2015).
3. Pardi, N. et al. J. Control. Release 217, 345–351 (2015).
specific for the CD4-binding site in monkeys will be used to solve the HIV problem and 4. Pardi, N. et al. J. Exp. Med. 215, 1571–1588 (2018).
and humans11. eOD-GT8 has now been that this will be tackled with the same sense 5. Chaudhary, N., Weissman, D. & Whitehead, K. A. Nat. Rev. Drug
converted into an mRNA vaccine through of urgency, given that HIV remains a major Discov. 20, 817–838 (2021).
6. Mu, Z., Haynes, B. F. & Cain, D. W. Vaccines 9, 134 (2021).
the same platform as the successful Moderna global health challenge. ❐ 7. Khoury, D. S. et al. Nat. Med. 27, 1205–1211 (2021).
vaccine against COVID-19, with human 8. Lederer, K. et al. Immunity 53, 1281–1295.e5 (2020).
clinical trials due to start soon. Lynn Morris   1,2 ✉ 9. Gray, G. E. et al. N. Engl. J. Med. 384, 1089–1100 (2021).
10. Corey, L. et al. N. Engl. J. Med. 384, 1003–1014 (2021).
There is no doubt that HIV presents 1
Antibody Immunity Research Unit, Faculty of
11. Jardine, J. G. et al. Science 351, 1458–1463 (2016).
a much greater challenge for vaccine Health Sciences, University of the Witwatersrand,
developers than COVID-19 does. The Johannesburg, South Africa. 2Center for the AIDS Competing interests
vast genetic diversity and the ability of Program of Research in South Africa, University of The author declares no competing interests.

2084 Nature Medicine | VOL 27 | December 2021 | 2078–2084 | www.nature.com/naturemedicine