Both vaccination and natural infection with SARS-CoV-2 reduce the risk of re-infection and severe COVID-19. Patients who have developed antibodies to coronavirus in response to natural infection have 89% protection against re-infection. The effectiveness of the vaccine is from 50 to 95%.

Since immune responses weaken over time and protect less against new strains of SARS-CoV-2, it is unknown how much coronavirus immunity lasts. One of the indicators by which one can judge how much a person is protected from SARS-CoV-2 infection is the level of neutralizing antibodies.

Australian scientists investigated how antibody levels after vaccination affect protection against SARS-CoV-2 infection. Scientists summarized data on neutralizing antibody titers from phase 1 and 2 vaccine trials and studies involving patients recovering from COVID-19:

All vaccine trials used different methods of measuring neutralization and other criteria for recovery. Therefore, for each study, the scientists proposed normalizing the neutralizing antibody titers to the mean convalescent titer used in the same study.

The researchers then compared this normalized level of neutralizing antibodies in each study with the corresponding protective efficacy reported in seven phase 3 vaccine trials:

The researchers found a strong non-linear relationship between normalized neutralizing antibody levels and reported vaccine efficacy (Figure 1a).

Figure 1. Relationship between neutralization rate and protection against SARS-CoV-2 infection

a. Shown are the mean neutralization rates from the Phase 1 and 2 trials and the protective efficacy from the Phase 3 trials for seven vaccines, as well as the protection observed in the seropositive recovering cohort.

A green circle indicates the mean level of neutralization and protective efficacy of the Covaxin vaccine since the data from this study were available only after the completion of the modeling and were not involved in the selection.

b. Modeling the protective neutralization level. Data for each study include the distribution of the measured in vitro neutralization titer against SARS-CoV-2 in vaccinated or recovering subjects.

The dotted line is the mean titer in convalescent subjects.

The bell curve is the level of protective effectiveness. Effectiveness is illustrated by the proportions of the “protected” (blue) and “receptive” (red) bell curves.

The solid blue line is the optimal level of protective neutralization of 50% (half the chance of getting infected compared to an unvaccinated person).

Source: https://www.nature.com/articles/s41591-021-01377-8

Neutralizing Antibodies: What Level Protects Against COVID-19

The researchers adapted previous approaches to assessing the protective titer of antibodies against influenza and applied them to the mean neutralization data in the present study. They found that the 50% protective level of neutralizing antibodies is 20% of the mean convalescent titer (Fig. 1a, b).

A 50% protective neutralization level, equivalent to 20% of the mean titer in convalescent subjects, corresponds to an in vitro measured neutralization titer of 1:10 to 1:30 in most of the assays described, estimated to be about 54 IU / ml.

Predicting Vaccine Effectiveness 

The mean neutralization rate measured early after vaccination can predict the protective efficacy in Phase 3 studies.

The estimated 50% neutralization rate for SARS-CoV-2 is 20% of the convalescent median titer. Scientists have calculated the effectiveness of the Covaxin vaccine (BBV152). The predicted efficacy of the vaccine is 79.6%, which is in very close agreement with the reported efficacy of 80.6% and confirms the predictive value of the method.

How Many Antibodies Persist After Vaccination

Recent studies have shown that neutralizing antibody titers decline 8 months after infection with SARS-CoV-2. Scientists have analyzed the dynamics of neutralizing antibody titers after vaccination and compared it with the dynamics of titers convalescent from COVID-19. The vaccine and natural infection results were similar: neutralizing antibody titers were halved after 65 days for vaccination and after 58 days for natural SARS-CoV-2.

This data makes it possible to predict how a decrease in neutralization titers will affect the vaccine’s effectiveness. However, there are several caveats to such a predictive model:

  • It suggests that neutralizing antibodies are the primary defense mechanism (or that it remains correlated with neutralization over time). However, B cell memory and T cell responses may be more robust and play a more significant role later after infection or vaccination.
  • She applies the reduction in neutralizing antibody titer seen during convalescence to the vaccine data.
  • It assumes that the decrease in antibody titer is independent of the starting level. However, other studies have shown faster or slower titer declines for higher starting levels.

With this in mind, the researchers analyzed the half-life of the neutralization titer using titer data from convalescent patients over 8 months after infection. Result: The neutralizing antibody titer is halved in 108 days (Fig. 2b).

The scientists then simulated the breakdown of neutralizing antibodies during the first 250 days after vaccination (Fig. 2a). Even if the decrease in neutralization titer over time is the same for different vaccines, this decrease will not be linearly reflected in the level of protection against SARS-CoV-2 infection as it will depend on the initial effectiveness of the vaccine. For example, a vaccine with an initial efficacy of 95% is expected to be 77% effective after 250 days. However, for a vaccine with an initial efficacy of 70% after 250 days, the effectiveness will drop to 33%. This model can be used to predict the timing of revaccination.

Figure 2. Effect of reducing neutralizing antibody titer on protection against SARS-CoV-2 infection

a. Evaluating the decline in efficacy of vaccines with different levels of initial efficacy.

b. Estimated time for efficacy to decline to 70% (red line) or 50% (blue line) for vaccines with different initial efficacy.

c. Assessing the impact of variations in coronavirus on vaccine efficacy. In vitro studies have shown that neutralization titers against some variants of SARS-CoV-2 are reduced compared to titers against wild-type viruses. The difference in the level of neutralization can predict the difference in the effectiveness of protection against wild-type and variant viruses. The dotted line indicates equal protection against wild-type and variant strains.

Source: https://www.nature.com/articles/s41591-021-01377-8

How Effective Is The Vaccine Against New Strains Of Coronavirus

In addition to decreasing neutralizing antibody titers over time, research has shown that vaccines are less protective against new strains of coronavirus. For example, the titer of neutralizing antibodies against the South African strain in vaccinated individuals is 7.6-9 times lower than against the early Wuhan strain.

Australian scientists hypothesize that a lower neutralization titer against new strains will have a more substantial effect on vaccines for which the protective efficacy against wild-type virus was lower (Fig. 2c).

For example, a five-fold lower neutralization titer is predicted to reduce efficacy from 95% to 77% for a vaccine with high efficacy and 70% to 32% for a vaccine with a lower initial efficacy.

What Level of Neutralizing Antibodies Protects Against Severe Coronavirus

The above analysis examines the protection provided by the vaccine and natural infection against symptomatic coronavirus. However, the immune response protects better against severe conditions than mild infections.

Scientists analyzed data on the level of protection against severe infection. As with symptomatic infection, the definitions of severe infection differed across studies. All phase 3 studies reported fewer than 100 severe infections.

The neutralizing antibody level for 50% protection against severe infection is 3% of the average recovering level. This figure is well below the 20% level required to protect against the symptomatic disease of any severity.

There is a caveat to this model: it is assumed that the neutralization titer itself protects against severe infection. However, T-cell and memory B-cell responses are also crucial in protecting against severe disease.

Conclusions

By the titer of neutralizing antibodies, one can predict the vaccine’s effectiveness and plan the timing of revaccination against COVID-19. As the level of offsetting antibodies decreases, the protection against SARS-CoV-2 diminishes. New immunizations may be required during the year. However, the level of neutralizing antibodies to protect against severe infection is 6 times lower than that needed to protect against the symptomatic disease of any severity. Therefore, protection against severe illness can be significantly more robust given the effect of T cells and memory B cells.

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Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection

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