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Accelerating COVID-19 Vaccine Testing with ‘Correlates of Protection’

Posted on by Dr. Francis Collins

Women walking with two insets showing 1. Few antibodies labeled "Vaccine efficacy of 78%" and 2, many antibodies labeled, "Vaccine efficacy of 98%

With Omicron now on so many people’s minds, public health officials and virologists around the world are laser focused on tracking the spread of this concerning SARS-CoV-2 variant and using every possible means to determine the effectiveness of our COVID-19 vaccines against it. Ultimately, the answer will depend on what happens in the real world. But it will also help to have a ready laboratory means for gauging how well a vaccine works, without having to wait many months for the results in the field.

With this latter idea in mind, I’m happy to share results of an NIH-funded effort to understand the immune responses associated with vaccine-acquired protection against SARS-CoV-2 [1]. The findings, based on the analysis of blood samples from more than 1,000 people who received the Moderna mRNA vaccine, show that antibody levels do correlate, albeit somewhat imperfectly, with how well a vaccine works to prevent infection.

Such measures of immunity, known as “correlates of protection,” have potential to support the approval of new or updated vaccines more rapidly. They’re also useful to show how well a vaccine will work in groups that weren’t represented in a vaccine’s initial testing, such as children, pregnant women, and those with certain health conditions.

The latest study, published in the journal Science, comes from a team of researchers led by Peter Gilbert, Fred Hutchinson Cancer Research Center, Seattle; David Montefiori, Duke University, Durham, NC; and Adrian McDermott, NIH’s Vaccine Research Center, National Institute of Allergy and Infectious Diseases.

The team started with existing data from the Coronavirus Efficacy (COVE) trial. This phase 3 study, conducted in 30,000 U.S. adults, found the Moderna vaccine was safe and about 94 percent effective in protecting people from symptomatic infection with SARS-CoV-2 [2].

The researchers wanted to understand the underlying immune responses that afforded that impressive level of COVID-19 protection. They also sought to develop a means to measure those responses in the lab and quickly show how well a vaccine works.

To learn more, Gilbert’s team conducted tests on blood samples from COVE participants at the time of their second vaccine dose and again four weeks later. Two of the tests measured concentrations of binding antibodies (bAbs) that latch onto spike proteins that adorn the coronavirus surface. Two others measured the concentration of more broadly protective neutralizing antibodies (nAbs), which block SARS-CoV-2 from infecting human cells via ACE2 receptors found on their surfaces.

Each of the four tests showed antibody levels that were consistently higher in vaccine recipients who did not develop COVID-19 than in those who did. That is consistent with expectations. But these data also allowed the researchers to identify the specific antibody levels associated with various levels of protection from disease.

For those with the highest antibody levels, the vaccine offered an estimated 98 percent protection. Those with levels about 1,000 times lower still were well protected, but their vaccine efficacy was reduced to about 78 percent.

Based on any of the antibodies tested, the estimated COVID-19 risk was about 10 times lower for vaccine recipients with antibodies in the top 10 percent of values compared to those with antibodies that weren’t detectable. Overall, the findings suggest that tests for antibody levels can be applied to make predictions about an mRNA vaccine’s efficacy and may be used to guide modifications to the current vaccine regimen.

To understand the significance of this finding, consider that for a two-dose vaccine like Moderna or Pfizer, a trial using such correlates of protection might generate sufficient data in as little as two months [3]. As a result, such a trial might show whether a vaccine was meeting its benchmarks in 3 to 5 months. By comparison, even a rapid clinical trial done the standard way would take at least seven months to complete. Importantly also, trials relying on such correlates of protection require many fewer participants.

Since all four tests performed equally well, the researchers say it’s conceivable that a single antibody assay might be sufficient to predict how effective a vaccine will be in a clinical trial. Of course, such trials would require subsequent real-world studies to verify that the predicted vaccine efficacy matches actual immune protection.

It should be noted that the Food and Drug Administration (FDA) would need to approve the use of such correlates of protection before their adoption in any vaccine trial. But, to date, the totality of evidence on neutralizing antibody responses as correlates of protection—for which this COVE trial data is a major contributor—is impressive.

Neutralizing antibody levels are also now being considered for use in future coronavirus vaccine trials. Indeed, for the EUA of Pfizer’s mRNA vaccine for 5-to-11-year-olds, the FDA accepted pre-specified success criteria based on neutralizing antibody responses in this age group being as good as those observed in 16- to 25-year-olds [4].

Antibody levels also have been taken into consideration for decisions about booster shots. However, it’s important to note that antibody levels are not precise enough to help in deciding whether or not any particular individual needs a COVID-19 booster. Those recommendations are based on how much time has passed since the original immunization.

Getting a booster is a really good idea heading into the holidays. The Delta variant remains very much the dominant strain in the U.S., and we need to slow its spread. Most experts think the vaccines and boosters will also provide some protection against the Omicron variant—though the evidence we need is still a week or two away. The Centers for Disease Control and Prevention (CDC) recommends a COVID-19 booster for everyone ages 18 and up at least six months after your second dose of mRNA vaccine or two months after receiving the single dose of the Johnson & Johnson vaccine [5]. You may choose to get the same vaccine or a different one. And, there is a place near you that is offering the shot.


[1] Immune correlates analysis of the mRNA-1273 COVID-19 vaccine efficacy clinical trial.
Gilbert PB, Montefiori DC, McDermott AB, Fong Y, Benkeser D, Deng W, Zhou H, Houchens CR, Martins K, Jayashankar L, Castellino F, Flach B, Lin BC, O’Connell S, McDanal C, Eaton A, Sarzotti-Kelsoe M, Lu Y, Yu C, Borate B, van der Laan LWP, Hejazi NS, Huynh C, Miller J, El Sahly HM, Baden LR, Baron M, De La Cruz L, Gay C, Kalams S, Kelley CF, Andrasik MP, Kublin JG, Corey L, Neuzil KM, Carpp LN, Pajon R, Follmann D, Donis RO, Koup RA; Immune Assays Team§; Moderna, Inc. Team§; Coronavirus Vaccine Prevention Network (CoVPN)/Coronavirus Efficacy (COVE) Team§; United States Government (USG)/CoVPN Biostatistics Team§. Science. 2021 Nov 23:eab3435.

[2] Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R, Diemert D, Spector SA, Rouphael N, Creech CB, McGettigan J, Khetan S, Segall N, Solis J, Brosz A, Fierro C, Schwartz H, Neuzil K, Corey L, Gilbert P, Janes H, Follmann D, Marovich M, Mascola J, Polakowski L, Ledgerwood J, Graham BS, Bennett H, Pajon R, Knightly C, Leav B, Deng W, Zhou H, Han S, Ivarsson M, Miller J, Zaks T; COVE Study Group. N Engl J Med. 2021 Feb 4;384(5):403-416.

[3] A government-led effort to identify correlates of protection for COVID-19 vaccines. Koup RA, Donis RO, Gilbert PB, Li AW, Shah NA, Houchens CR. Nat Med. 2021 Sep;27(9):1493-1494.

[4] Evaluation of the BNT162b2 Covid-19 vaccine in children 5 to 11 years of age. Walter EB, Talaat KR, Sabharwal C, Gurtman A, Lockhart S, Paulsen GC, Barnett ED, Muñoz FM, Maldonado Y, Pahud BA, Domachowske JB, Simões EAF, Sarwar UN, Kitchin N, Cunliffe L, Rojo P, Kuchar E, Rämet M, Munjal I, Perez JL, Frenck RW Jr, Lagkadinou E, Swanson KA, Ma H, Xu X, Koury K, Mather S, Belanger TJ, Cooper D, Türeci Ö, Dormitzer PR, Şahin U, Jansen KU, Gruber WC; C4591007 Clinical Trial Group. N Engl J Med. 2021 Nov 9:NEJMoa2116298.

[5] COVID-19 vaccine booster shots. Centers for Disease Control and Prevention. Nov 29, 2021.


COVID-19 Research (NIH)

COVID-19 Prevention Network

Combat COVID (U.S. Department of Health and Human Services)

Peter Gilbert (Fred Hutchison Cancer Research Center)

David Montefiori (Duke University, Durham, NC)

Adrian McDermott (National Institute of Allergy and Infectious Diseases/NIH)

NIH Support: National Institute of Allergy and Infectious Diseases


  • JJ Sikora says:

    There are two vaccines that have been sent to the FDA for consideration. One is Astrozenica’s antibody cocktail, and the other is Novamax whose clinicals show strong effectiveness for the SAR-2 virus which is the backbone of the viruses we are currently fighting. If only phyzer and moderna and j&j are allowed…we may have lost something better.

  • VICENTE says:

    Excellency for helping patients of the world . . .

  • Zuccheri Gianni says:


    I thank Dr. Collins for this article and for the opportunity to present a particular clinical case.

    A patient with glaucoma sends me his brain-orbit Magnetic resonance imaging (MRI), performed a few days ago.
    He is concerne about the description of the optic nerve in his right eye damaged by high eye pressure. In fact, he came to visit last summer without ever having been in hypotonic therapy, the visual field of right eye is badly lost.

    I also prescribed MRI , not limiting myself to the hypothesis of simple ocular hypertension.
    The reason is the young age of the patient, 36 years.
    I pay attention to him, as I noticed a constant and marked folate (vitamin B 9) deficiency (it causes neurodegenerative diseases):
    repeated the dosage several times, it became sufficient only with constant daily folic acid administration.
    Adequate nutrition alone was not sufficient, but no other deficits nor the presence of malabsorption, such as celiac disease, were evident.

    This additional trait confirms the definition that the Glaucoma is a multifactorial disease, with very varied and sometimes unexpected aspects, which accompany or exclude each other from time to time.
    But why am I talking about Glaucoma and folate deficiency in a section dedicated to Covid19 and related vaccines?
    Simple: the young man is sick at home with Covid, so far nothing exceptional.

    Finally, he tells me he was already SARS-CoV-2 infected in January 2021, vaccinated with two doses of Pfeizer mRNA a few months later and now the second time Covid19 disease .

    I come to express the consideration that both in neurodegenerative diseases, for example Glacoma, and the immune response to infectious agents is mediated by individual factors
    ( ) that sometimes escape if disconnected from the overall clinical context of the patient.

    An individual can get ill with a neurodegenerative disease due to vitamin deficiencies which at the same time compromise
    white blood cells, predisposing to infections.

    Reading with interest what the studies related to the evaluation of antibody levels report, as explained by the NIH Director Dr. Collins,
    “::Antibody levels also have been taken into consideration for decisions about booster shots.::” ,

    I think it would be very useful in cases like the one I mentioned..

  • Mike says:

    There is a difference between IgM antibodies and IgG antibodies. Not to mention IgE antibodies. As for epitope mapping, there is well known correlation with that and auto-immune diseases such as multiple sclerosis. Coronavirus buds from cells it infects. I am sure the virologists at the NIH are well versed in cell biology of that and the history of adenoviral vector HIV vaccines. But then again, there is the public health aspect and the type of people who control that trajectory. That is not just limited to science it would seem.

  • Zuccheri Gianni says:

    I refer to the glaucoma patient I mentioned earlier.

    The question.
    At the first Covid19 episode and during vaccinations, he had no ocular therapy.

    At the second episode Covid19 he was taking eye drops composed of timolol (beta blocker) and a prostaglandin analogue drug.
    Together with the folate deficiency, this drug therapy could interfere with the body’s response to viral aggression, since an entry gate for the virus is the ocular mucous membranes.
    Furthermore, through the lacrimal tract, the eye drops descend into the upper airways: this is also an important entry route for SARS-CoV-2. ACE2 receptors are present on both membranes, ocular and nasal:
    Do glaucoma eye drops play a role in this whole scenario? and what part do IgA play? Hypothetical interference between these factors, ACE2 receptors and the viral particle?
    Would it also be useful to have a rapid IgA search test to understand the degree of effective immunity?

  • Zuccheri Gianni says:

    While I was sending my comment for your blog, I casually listened to your closing speech with a splendid performance of singing with guitar: a moving moment!

    I repeat my previous comment:

    “..when I was a young doctor, my head physician one day told me:
    “If I hadn’t made this passionate profession I would have liked to be a tenor singer, to brighten people’s lives with my singing”

    I believe that whoever practices science and at the same time music or singing, doubles the result of his work.

    I want to renew the congratulations to Dr. Collins and the NIH for the work of research and treatment ..”

  • Raysal R. says:

    This is helpful for the world.

  • Delmar says:

    The problem that I have with the study is that they grouped all people of color together as if they were one homogeneous monolith. They need to show results by individual community. There are more haplogroups among people of African descent than any other group. How are they being lumped in with white Latinos, non-white Latinos, Pacific Islanders, Indigenous people, Asian people, and others? How are all these other people being lumped together as a homogeneous monolith? No one is a generic “person of color”. Everyone is a member of a particular community. The result for a generic “person of color” is really meaningless as it doesn’t address results for real people who are members of particular communities. It might have been more meaningful to have subgroups based on economics if this was an attempt somehow to incorporate the social vulnerability index. The disturbing trend in medicine to group people basically as white and “other” reinforces whiteness as somehow standard and normative and reinforces a white supremacist narrative.

  • n says:

    Thank you for sharing useful information keep on sharing.

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