Immunity following COVID-19 vaccination and natural infection in India

The coronavirus disease 2019 (COVID-19) was caused by infection with the severe acute respiratory syndrome coronavirus syndrome 2 (SARS-CoV-2) and has caused hundreds of millions of documented infections worldwide, besides five million deaths.

Study: Immunity to COVID-19 in India through vaccination and natural infection. Image Credit: REC Stock Footage/ Shutterstock

The virus enters the host through the nasal mucosa, binding to the angiotensin-converting enzyme 2 (ACE2) receptor for the virus on the host cell via its spike protein. The receptor-binding domain (RBD) is the area of the spike that engages with the receptor. Inhibition of the RBD-ACE2 binding would be effective in preventing infection or mitigating the severity of the disease.

Several vaccines have been developed to protect against the infection, including those built on nucleic acid platforms and virus vector platforms. In India, the Covishield vaccine has been widely distributed, with over 430 million doses administered so far. This is the Oxford–AstraZeneca chimpanzee adenovirus vectored vaccine ChAdOx1 nCoV-19 (AZD1222).

Another indigenous vaccine was rolled out later, called Covaxin, developed by Bharat Biotech, Hyderabad. This is an inactivated whole virus vaccine and was administered in “clinical trial mode.”

India saw a small first wave of COVID-19 in 2020, followed by a brutal second wave, driven by emerging variants of concern, especially the Delta virus variant.  

To avoid the danger of a third wave, India launched its vaccination drive, which administers millions of doses of vaccines each day. About a third of the population has received both doses so far.

The current study, available on the medRxiv* preprint server, seeks to compare the efficacy of these two vaccines and vaccine-elicited immunity vs. that induced by natural infection. The researchers evaluated immune response markers in a cross-section of people from the Indian state of West Bengal, including those vaccinated with either Covishield or Covaxin, the unvaccinated cohort, and the naturally infected.

An earlier study in the same state, focusing on Kolkata and its surroundings, by these authors showed 90% efficacy in eliciting an immune response for Covishield, against the wildtype virus. They estimated that about 40% of the population was infected at that point.

The second wave hit after that study was completed, beginning from the end of May 2021 and ending towards the last part of June. By July end, much of the city had received two doses of one of the above vaccines.

What did the study show?

The researchers measured neutralizing capacity and the T cell response to the virus in the naturally infected and vaccinated population. There were five patient groups:

• Groups 1 and 2 were vaccinated, had no history of infection.
• Group 3 was naturally infected but mostly asymptomatic, showing antibodies to the wildtype virus by the end of 2020.
• Group 4 comprised symptomatic infections, mostly hospitalized.
• Group 5 was the control group, without history of infection or vaccination.

Seroconversion rates

The researchers found that 90% of Covishield recipients (two doses) had anti-wildtype-RBD antibodies, whereas Covaxin had 84% effectiveness in seroconversion. Following infection, first wave individuals showed seroconversion in 82% vs. 86% in the second wave.

When examined for antibodies to the Delta variant, a similar profile was obtained. The antibody titers waned over time, with a couple landing below the cut-off for seropositivity at eight to 11 months from the time of the first test.

Neutralizing response

The study also showed that the plasma samples had varying neutralizing potential when it came to blocking the ACE2-RBD interaction in vitro. Earlier, they had shown that both RBDs were engaged by the ACE2 molecule with comparable efficiencies, and at approximately 50 ng ACE2, 100% binding was achieved.

Samples from Covishield-vaccinated individuals appeared to have high neutralizing efficiency against the wildtype RBD was low, as well as those infected during the second wave. For both Covaxin and the samples from first-wave infections, neutralization efficiency was low, especially the first-wave infections.

With the Delta RBD variant, neutralizing efficiency followed the same trends but at slightly lower levels. The authors also refer to the presence of seropositivity and neutralizing capacity in the control group, though much lower than in the other groups, indicating the potential for the presence of cross-reactivity against overlapping epitopes on the RBD.

In the presence of serum containing anti-RBD immunoglobulin (Ig) antibodies, ACE2 binding to the wildtype or Delta RBD was dramatically reduced. In contrast, antibody binding was observed instead, showing the specificity of the neutralizing antibodies in these patient samples.

Overall, these results suggest that while natural infection with SARS-CoV-2 is as effective as vaccination in generating an antibody response, this humoral immunity may not last long enough to fight off future infections. Whether the currently administered vaccinations will provide a long-term humoral immunity against the virus is a matter that only time will confirm.”

T Cell immunity

T cell responses following stimulation with the viral antigens, via vaccination or natural infection, were assessed in the form of gamma-interferon (IFNγ) responses within CD8+ and CD4+ T cells, this being an established antiviral cytokine; and CD40 ligand (CD40L/CD154) expression, since this is a marker of antigen-activated clonal expansion of these cells.

Here again, vaccination and natural infection were found to produce comparable IFNγ responses in both CD8+ and CD4+ T cells. The CD40L response was at a lower response than the IFNγ response.

With the Delta variant, all T cell responses were lower in the vaccinated groups than following natural infection, except for the CD8+CD40L response. Covaxin produced 2-3-fold higher T cell responses than Covishield, with this variant. There was a somewhat higher T cell response in the natural infection group compared to the wildtype RBD.

When the recall response to the antigen was tested, the same trend was seen. T cell responses to the wildtype RBD were comparable between natural infection and vaccinated groups. With the Delta variant, the T cell responses were higher after natural infection than vaccination, but the Covaxin group showed higher responses than the Covishield group.

This suggests that the T cell response to Covaxin is better than with Covishield, and that natural infection is superior to both vaccines in producing adaptive cellular immunity. The results also indicate that T cell immunity lasts for ten months following infection, while further follow-up will be required to assess the durability in vaccinated individuals.

What are the implications?

The study shows that vaccine-induced immunity effectively neutralizes the wildtype virus, with Covishield showing significantly higher effectiveness than Covaxin. While the efficiency of neutralization is lower, both vaccines neutralize the Delta variant, with a lesser margin between the two vaccines.

The highest neutralizing efficiency is seen with neutralizing antibodies induced by second wave natural infections, which out-performs both vaccines. Interestingly, this is not seen in individuals infected during the first wave, perhaps because of the absence of long-lived antibody secreting plasma cells.

T cell immunity is similar with either vaccine, with Covaxin outpacing Covishield when it comes to Delta variant immunity. Natural immunity produces comparably efficient cellular immunity and even better against the Delta variant. This immunity is durable, measured at ten months from the infection, indicating that memory T cells were raised after a single attack.

The different profile of the humoral and cellular immune response could be due to the variation in the frequency of the antigenic sites that bind to the antibody or T cell receptors in these two groups of individuals.

Despite the lack of a head-to-head comparison of vaccine efficacy against Delta variant infection vs. the immunity induced by natural infection, real-life shows a steep decline in severe COVID-19 cases and deaths after two doses of the vaccine are taken worldwide.

While breakthrough infections, even fatal ones, have been documented, most individuals were at high risk because of severe comorbidities. Therefore, the researchers conclude that both vaccines protect against both the wildtype and Delta variant of SARS-CoV-2, though they act in different ways. The observed gap between vaccine- and infection-induced immunity opens up the question of which will provide better long-term immunity to protect against future infections and efficiently control the pandemic.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.