The correct answer is:

Natural infection with the original SARS-CoV-2 virus as well as vaccination with any of the 3 currently available USA vaccines all show significantly decreased in vitro effectiveness against the Delta variant as compared to their effectiveness against the original SARS-CoV-2 virus.

Key Point:

A July 2021 in vitro study found antibodies against the original SARS-CoV-2 virus (either from the sera of post-convalescent or vaccinated patients) had diminished in vitro effectiveness against the Delta variant.

The Moderna vaccine conferred the most in vitro inhibition of the Delta variant, followed by the Pfizer vaccine, then convalescent serum, and last by the Johnson & Johnson vaccine (least in vitro inhibition of Delta variant).

Explanation:

This study tested the degree to which antibodies from infection with, or vaccination against, the original SARS-CoV-2 virus cross-protected against several SARS-CoV-2 variants.

The authors exposed serum from 4 sources (see below list) that contained antibodies to the original SARS-CoV-2 virus to various SARS-CoV-2 variants, among them the Delta variant:

(1)    post-convalescent people who had recovered from natural infection with the original SARS-CoV-2 virus 3 months ago,

(2)    people who received Pfizer’s 2-dose SARS-CoV-2 vaccine (second dose at 3 months ago),

(3)    people who received Moderna’s 2-dose SARS-CoV-2 vaccine (second dose at 3 months ago),

(4)    people who received Johnson & Johnson’s 1-dose SARS-CoV-2 vaccine (3 months ago).

The authors repeatedly diluted each sample in order to establish the lowest inhibitory concentration (IC50) at which the remaining (highly diluted) antibodies could still inhibit 50% of the original virus or a given SARS-CoV-2 variant. The below summary focuses on the study’s results for the Delta variant currently circulating in the USA.

The authors found that the various antibodies in response to natural infection or vaccination could tolerate the following degree of dilution before they lost their in vitro 50% effectiveness:

(1)    IC50 of Post-Infectious Serum (dilution that could still inhibit 50% of viral particles):

The mean IC50 of post-convalescent antibodies was IC50 = 346 against the original SARS-CoV-2 virus (benchmark) and decreased significantly to IC50 = 78 for the Delta variant (the antibodies tolerated a much lower degree of dilution before losing the ability to inhibit 50% of the virus).

(2)    IC50 of Pfizer’s 2-dose vaccination:

The mean IC50 of serum with antibodies after 2-dose Pfizer vaccination was IC50 = 695 against the original SARS-CoV-2 virus and decreased significantly to IC50 = 191 against the Delta variant.

(3)    IC50 of Moderna 2-dose vaccination:

The mean IC50 of serum with antibodies after 2-dose Moderna vaccination was IC50 = 833 against the original SARS-CoV-2 virus and decreased significantly to IC50 = 207 against the Delta variant.

(4)    IC50 of Johnson & Johnson 1-dose vaccination:

The mean IC50 of serum with antibodies after 1-dose Johnson & Johnson vaccination was IC50 = 221 against the original SARS-CoV-2 virus and decreased significantly to IC50 = 30 against the Delta variant.

Rearranged in descending order, these data showed:

Original SARS-CoV-2 Virus: Moderna IC50 833 (tolerated most dilution before losing 50% effectiveness); Pfizer IC50 695; convalescent IC50 346; Johnson & Johnson IC50 221 (tolerated least dilution before losing 50% effectiveness).

Delta Variant: Moderna IC50 207 (tolerated most dilution before losing 50% effectiveness); Pfizer IC50 191; convalescent IC50 78; Johnson & Johnson IC50 30 (tolerated least dilution before losing 50% effectiveness).

In order to translate these in vitro numbers into projected in vivo performance, the authors next applied the following currently accepted in vitro to in vivo correlation model:

Correlation #1: in vitro IC50 that translates into 50% in vivo protection from hospitalization:

COVID-19 modeling projects that a SARS-CoV-2 vaccine or post-convalescent serum that exhibits an in vitro IC50 against variant x that is at least 20% of the original IC50 exhibited by post-convalescent serum against the original SARS-CoV-2 virus (benchmark), then this vaccine/post-convalescent serum will protect 50% of people against moderate-severe disease from this specific SARS-CoV-2 variant x.

This means:

1. In this study, the in vitro IC50 was 346 for post-convalescent serum against the original SARS-CoV-2 virus (benchmark). Thus, a vaccine capable of attaining an IC50 of 69 (20% of 346) against variant x would be expected to protect 50% of vaccinated people from hospitalization due to infection with SARS-CoV-2 variant x.
2. The authors’ measured effectiveness against the Delta variant was, in descending order, IC50 207 (Moderna), IC50 191 (Pfizer), IC50 78 (post-convalescent), and IC50 30 (Johnson & Johnson).
3. Conclusion: Moderna and Pfizer outperformed the IC50 69 needed to protect 50% of vaccinated people from moderate-severe COVID-19 by a factor of 3, thus providing significantly more than 50% hospitalization protection against the Delta variant. Natural infection only slightly exceeded this benchmark, thus providing about 50% hospitalization protection;  the Johnson & Johnson vaccine did not reach the IC50 of 69 benchmark, thus likely providing less than 50% hospitalization protection against the Delta variant.

Correlation #2 - in vitro IC50 that translates into 50% in vivo protection from Critical Disease:

COVID-19 modeling projects that a SARS-CoV-2 vaccine or post-convalescent serum that exhibits an in vitro IC50 against variant x that is at least 3% of the original IC50 exhibited by post-convalescent serum against the original SARS-CoV-2 virus (benchmark), then this vaccine/post-convalescent serum will protect 50% of people against severe-critical disease/death from this specific SARS-CoV-2 variant x.

This means:

1. Starting from the same benchmark as for correlation #1 of IC50 of 346 for post-convalescent serum against the original SARS-CoV-2 virus, the 3% IC50 would be an IC50 of 10 (3% of 346). Thus, a vaccine capable of attaining an IC50 of 10 against SARS-CoV-2 variant x would be expected to protect 50% of vaccinated people from severe-critical COVID-19 due to variant x.
2. The same measured IC50 series against the Delta variant used for correlation #1 also applies to this calculation - in descending order, IC50 207 (Moderna), IC50 191 (Pfizer), IC50 78 (post-convalescent), and IC50 30 (Johnson & Johnson).
3. Conclusion: Moderna and Pfizer outperformed the IC50 10 needed to protect 50% of vaccinated people from severe-critical COVID-19 by a factor of 20, thus providing significantly more than 50% protection from severe-critical disease/death. Natural infection exceeded this benchmark by a factor of 8, thus also providing significantly more than 50% protection; the Johnson & Johnson vaccine exceeded this benchmark by a factor of 3, thus also providing more than 50% protection.

In other words, the in vitro results of this study suggest that post-convalescent serum as well as all 3 USA COVID-19 vaccines provide significant protection from severe-critical disease/death due to the Delta variant.

Only the 2-dose vaccines Pfizer and Moderna also provide significant protection from hospitalization due to infection with the Delta variant.

Past infection with the original COVID-19 virus provides somewhat more than 50% protection from hospitalization, and the Johnson & Johnson single-dose vaccine provides less than 50% protection against hospitalization due to infection with the SARS-CoV-2 Delta variant.

These calculations based on in vitro data must be understood with caution. For example, the authors point out that a recent in vivo study showed the Johnson & Johnson single-shot vaccine to provide 64% protection against hospitalization and 81.7% protection against severe-critical disease/death from the Beta variant. Given that the current study’s Johnson & Johnson vaccine’s IC50 for the Beta variant was 33 and for the Delta variant 30 (in other words, very similar), it is possible that the Johnson & Johnson vaccine’s actual (rather than projected) in vivo performance against the Delta variant (for which large in vivo data collections are lacking), would be more similar to the Beta variant (for which in vivo data exist). Stated more briefly: if the Johnson & Johnson vaccine indeed performs similarly against the Delta variant as it does against the Beta variant, then the vaccine’s performance may better than predicted by the above in vitro data and calculations.

A different July 2021 paper (Bernal) found that 2 doses of any COVID-19 vaccination might be necessary in order to protect against the Delta variant of SARS-CoV-2.

Bottom Line: Until guidelines regarding booster vaccinations against COVID-19 have been developed, clinicians might be able to use these data to consider the comparative risk of breakthrough infection in post-convalescent and fully vaccinated patients in a geographic area with high levels of circulating SARS-CoV-2 Delta variant.

This study did not explore the change in antibody performance as time elapsed since infection or last vaccination.

References:

Takuya T, et al. Comparison of Neutralizing Antibody Titers Elicited by mRNA and Adenoviral Vector Vaccine against SARS-CoV-2 Variants. bioRxiv 2021.07.19.452771 (This article is a preprint and has not been certified by peer review)

Bernal JL, et al. Effectiveness of Covid-19 Vaccines against the B.1.617.2 (Delta) Variant. The New England Journal of Medicine. July 21, 2021 DOI: 10.1056/NEJMoa2108891