Science - USA (2022-01-07)

INSIGHTS | PERSPECTIVES

22 7 JANUARY 2022 • VOL 375 ISSUE 6576 science.org SCIENCE

GRAPHIC: V. ALTOUNIAN/

SCIENCE

CORONAVIRUS

Using correlates to accelerate vaccinology

ByPeter J. M. Openshaw

T

here have been many reports of large-

scale vaccine studies showing that

various severe acute respiratory syn-

drome coronavirus 2 (SARS-CoV-2)

vaccines give almost complete protec-

tion against severe COVID-19 and in-

complete but dwindling protection against

infection of the nose and lungs. Given the

costs and difficulty of field studies involving

thousands of people, which are necessary to

show vaccine efficacy, the hunt for immune

correlates of protection (COPs; laboratory

measurements that predict the outcomes of

large-scale studies) has become intense. On

pa ge 43 of this issue, Gilbert et al. ( 1 ) re-

port the use of a technique called mediation

analysis to examine data from a trial of the

mRNA-1273 vaccine from Moderna to infer

that virus neutralizing antibody (VN-Ab)

accounts for ~60% of protection. They pro-

pose that VN-Abs might provide a reliable

COP, which could be used to support the ap-

proval of future COVID-19 vaccines, bypass-

ing the need for large trials.

Vaccines create resistance to infection by

creating a set of immunological barriers that

are deployed at different phases of patho-

gen entry and replication. These immune

responses control engagement of the virus

with target host cells in the nose and lungs,

suppress the propagation of infection within

the mucosa, modulate the inflammatory

response to viral invasion, and inhibit the

dissemination of the virus with consequent

extrapulmonary involvement in those with

severe disease (see the figure). Understanding

the immunology that underlies protection is

of great value to enable monitoring of vac-

cine duration and protective efficacy, as well

as in aiding the development of new or im-

proved vaccines that induce key elements of

the protective immune response. Any single

measure of immunity, however convenient,

is never going to reflect this multilayered

response. Therefore, can one measure suffi-

ciently reflect the full palette of immune re-

sponses and thus reliably predict protection?

The discovery of reliable COPs can be game-

changing in the production and licensure of

vaccines. For example, influenza vaccines are

updated twice a year according to the preva-

lent and projected circulating strains of influ-

enza virus, based on the ability of an updated

vaccine to induce an antibody response in a

small group of volunteers, bypassing the need

for large, slow, and expensive field trials. The

use of such a correlate depends on a clear

definition of the type of protection that is re-

quired and a solid relationship between the

measure and the desired outcome.

In assessing the effects of vaccines de-

signed to prevent COVID-19, VN-Abs, as

described by Gilbert et al., are a logical and

measurable target. VN-Abs coat virus parti-

cles, thereby preventing virus entry into cells.

However, protection induced by two doses

of messenger RNA (mRNA) vaccine may

not last, declining to nonprotective levels in

some vaccinees after 5 or 6 months ( 2 ). B y

focusing on an early serological COP, the op-

portunity may be missed to develop vaccines

that mediate broad and durable protection.

T cell responses may be important in sup-

porting VN-Ab–mediated protection and

helping to maintain long-term protection,

but each component of immune memory

National Heart and Lung Institute, Imperial College London,

London, UK. Email: [email protected]

PERSPECTIVES

C orrelates and surrogates of desired outcomes are valuable but have limitations

01 234 56 789 10 11 12 13 14 15 16 17 18 19 20 21

Viral phase

Virus entry

Establishment

of mucosal

infection

Viral replication

Viral clearance

Day 22+

Mucosal

virus–specific

immunoglobulin

(IgA, etc.)

Innate defenses

Interferons

Macrophage activation

T cells, ADCC

VN-Abs

Neutrophil activation

Systemic IgG, resident innate cells

Cytokines and

chemokines,

CXCL2, CXCL10

ADCC, antibody-dependent cellular cytotoxicity; CXCL, C-X-C chemokine ligand; GM-CSF, granulocyte-macrophage colony-stimulating factor; Ig, immunoglobulin;

IL, interleukin; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TNF, tumor necrosis factor; VN-Abs, virus-neutralizing antibodies.

Persistence of inammation

and organ damage (sometimes)

Inflammatory phase

TNF, IL-6, IL-8, GM-CSF

Resolution and convalescence

Sequential events during SARS-CoV-2 infection

The immunopathogenesis of COVID-19 can be depicted as an early viral phase followed by an inflammatory phase, which may be restricted or spread outside the

respiratory tract. Immune control occurs at various stages (teal arrows), whereas inflammation is important in disease pathogenesis (red arrows). Local and systemic

immunoglobulins operate at multiple levels, direct and indirect; VN-Abs are detectable from approximately day 10 for at least 3 months.