COVID-19 vaccines: Are two shots enough?

The latest SARS-CoV-2 mutant to join the league of WHO-declared variant of concern (VOC) —B.1.617.2 (now known as the Delta variant) — has sparked global concern, and for good reasons. 

First detected in India early this year, the Delta variant has taken over the world by storm and shows no sign of slowing down. It is now present on every continent (except Antarctica) in 74 countries, up from 40+ countries just a month ago, according to a recent epidemiological report from the WHO.

Armed with new mutations at E484Q and L452R, the Delta variant is more infectious and resistant to COVID-19 vaccines than other forms of variants. Now, health officials are worried it may also cause more severe disease requiring hospitalization.

Based on early findings (n=38,805) from Public Health England (PHE), COVID-19 cases caused by the Delta variant were 2.61 times more likely to be hospitalized within 14 days of specimen sampling compared with those infected with the Alpha variant (previously known as B.1.1.7). 

Nonetheless, vaccines appeared to be able to rein in the expansion of the Delta variant, at least to a certain extent.

Don’t stop at one

According to PHE, 73 percent of Delta cases occurred in unvaccinated people, compared with 3.7 percent among those who have been fully vaccinated with two doses.

Amidst concern that the Delta variant was more resistant to COVID-19 vaccines, some consolation came from what was the first known real-world data on vaccine efficacy against the variant, released in end May.

The study, spearheaded by PHE, showed that two doses of the BNT162b2 vaccine was 88 percent effective (95 percent confidence interval [CI], 78.2–93.2) against symptomatic COVID-19 caused by Delta. The corresponding effectiveness for the ChAdOx1 nCoV-19 vaccine was 60 percent (95 percent CI, 28.9–77.3). [medRxiv (preprint) 2021;doi:10.1101/2021.05.22.21257658]

For both vaccines, effectiveness was low against Delta after just one dose of vaccination, at 33 percent — highlighting the importance of completing the full course of vaccination.  

“[With just one dose of vaccine,] we found an absolute reduction of … approximately 20 percent [in vaccine effectiveness] against symptomatic disease [due to] the Delta variant … when compared to the Alpha variant,” the researchers noted. “However, reductions in vaccine effectiveness after two doses were very small.”

Vaccine effectiveness against the Alpha variant was 93.4 percent for BNT162b2 and 66.1 percent for ChAdOx1 nCoV-19, after two doses. 

The latest real-world data by PHE, released in June as a preprint, revealed that the protection was even higher against more severe COVID-19 requiring hospitalization. The analysis included 14,019 symptomatic Delta cases — of whom 166 were hospitalized.

After two doses of vaccination, effectiveness was 96 percent and 92 percent for the BNT162b2 and ChAdOx1 nCoV-19 vaccines, respectively, in preventing hospitalization due to the Delta variant.

“The way out is to vaccinate — fully vaccinate — as many people as possible as quickly as possible,” urged Professor Christina Pagel from University College London, London, UK, who also served as a member of the UK Independent Scientific Advisory Group for Emergencies. [BMJ 2021;373:n1346]

Two for all, except…

Barring the single-shot Ad26.CoV2.S vaccine, all vaccines available on the market require two doses to complete the course.

Yet, some have questioned the need to vaccinate people who had previously been infected with SARS-CoV-2 and would already have immunity in their body. 

However, experts currently do not know how strong and how durable is the immunity generated from a previous infection. There have also been anecdotes of COVID-19 survivors getting reinfected again. Hence, they urged even those who have recovered to get vaccinated.

The good news is that in people with a previous infection, high immune response was seen after just one dose of mRNA vaccine — at levels parallel to that after two standard doses in infection-naïve individuals. By contrast, giving the second shot to those previously infected led to little increase in antibody titres. [N Engl J Med 2021;384:1372-1374; Euro Surveill 2021;doi:10.2807/1560-7917.ES.2021.26.6.2100096]

“Changing the current vaccine recommendation to provide only one dose of vaccine to COVID-19 survivors would free up many urgently needed vaccine doses,” experts suggested.  [EBioMedicine 2021;doi:10.1016/j.ebiom.2021.103401]

Are two enough?

While the high vaccine effectiveness against hospitalization due to Delta infection is somewhat a relief, at least for the time being, it does not completely prevent it, let alone deaths from the disease.

Breakthrough infections still occurred — leading to a number of deaths in Delta cases, even after two doses of vaccination, based on PHE report. 

Hints that the Delta variant could be more resistant to COVID-19 vaccines than other existing variants have surfaced in an earlier study. Researchers tested serum samples from 250 participants who had been fully vaccinated with the BNT162b2 vaccine against exposure to several variants of SARS-CoV-2. [Lancet 2021;doi:10.1016/S0140-6736(21)01290-3]

Among the variants, neutralizing antibody response was reduced by the greatest extent — at 5.8 times lower — against Delta vs that against the wild-type SARS-CoV-2. The corresponding reductions were 2.6-fold lower against Alpha and 4.9-fold lower against Beta (previously B.1.351), compared with the original virus.

The question then, is whether two doses of vaccination are really enough? Or are further booster jabs required?   

“Notably, across all variants, increased age significantly correlated with reduced neutralizing antibody titres [NAbTs],” noted researchers of the Lancet study, led by Dr David Bauer of Francis Crick Institute, London, UK. 

Apart from age, they also found that the antibody neutralizing activity tended to wane with increasing time after the second vaccine dose, in particular with regard to the Beta and Delta variants.  

Both factors of increased age and time also happen to be characteristic of those at highest risk of severe illness from COVID-19 — ie, the older population who were also vaccinated earlier.

“[The association was] independent of other existing factors such as compromised immune status or comorbidity, or geographic-specific responses to vaccination,” Bauer and co-authors pointed out.

“Consequently, further booster immunizations of JCVI* Priority Groups in the UK and similar groups in other counties, as well as others with lower vaccine-induced NAbTs than the cohort of BNT162b2 recipients studied here … are more likely to be required to maintain the highest levels of neutralizing antibodies in regions where B.1.617.2 or other equally neutralizing antibody-resistant strains become prevalent,” they suggested. 

Make it three: For transplant patients

“The antibody response after two doses of an mRNA vaccine against SARS-CoV-2 is excellent in the general population, but the response is different in recipients of solid organ transplants,” according to researchers of a separate study on vaccination in transplant patients.

This group of patients belong to the immunosuppressed population as they need to rely on long-term immunosuppressant to prevent transplant rejection. Furthermore, they are at high risk for severe COVID-19 illness once infected.

Previous studies have indicated that almost half of solid organ transplant recipients (46 percent) did not show antibody response even after two shots of mRNA vaccines. Even in those who did respond positively to initial vaccination, the response was often more muted compared with healthy individuals. Hence, vaccination does not necessarily equate to immunity in these patients. [JAMA 2021;325:2204-2206]

In a recent study, researchers tracked 30 recipients (median age 57 years) of solid organ transplants who received a third dose of vaccination, after showing suboptimal response to the standard two doses of mRNA vaccines. The third vaccination involved either the Ad26.COV2.S vaccine or any of the mRNA vaccines. [Anns Int Med 2021;doi:10.7326/L21-0282]

“It is encouraging that antibody titres increased after the third dose in one third of patients who had negative antibody titres and in all patients who had low-positive antibody titres,” reported the researchers.

“We believe that these observations support the use of clinical trials to determine whether booster doses to prevent COVID-19 in transplant patients can be incorporated into clinical practice, as they have been for hepatitis B and influenza vaccination,” they added.

Already, trials are underway — at least for the mRNA vaccines — to study if a third jab is required to boost immunity which may wane over time or to cope with new viral variants.  

 

*JCVI: The Joint Committee on Vaccination and Immunisation