A Delayed Transition to Endemic

We should return to health protocols in anticipation for an increase in cases potentially sparked by the new subvariants. In so doing, we are preventing new variant infections from spiking.


About a month ago the government stated that we were entering a transitional period from the pandemic to endemic.

It was an encouraging statement, justifiably supported by the fact that one month after the government allowed long homecoming holidays for Idul Fitri celebrations, a worrying caseload escalation did not occur.

Amid this optimism, the daily cases started to trickle up. In fact, the average daily addition of cases had been hovering below 500 cases since May, with the data from 16 May even recording only 182 additional daily cases. This made many people optimistic about the prospect of the pandemic turning into an endemic soon.

This suddenly changed when daily cases continued to rise. As many as 551 new cases were recorded on 12 June. They increased to 1,241 cases on 15 June, before soaring to 2,069 cases on 23 June. It turned out the caseload surpassed the previous record high 1,907 during the receding period. So, it was understandable that many were starting to worry and be wary of this upward trend.

The increasing trend in daily cases occurred amid news about the finding of “uninvited guests”, namely the new variants BA.4 and BA.5, which were first reported to have entered Indonesia on June 6. A resident tested positive for BA.4 and showed no symptoms of the disease (asymptomatic). The patient was reported to have received the second dose of vaccine. Three people were detected as positive for B.5. Either asymptomatic or having mild symptoms, all three had received the third or even fourth dose of vaccines.

They were foreign travelers, who arrived in Indonesia to participate in the Global Platform for Disaster Risk Reduction meeting in Bali from 23 to 28 May. While the discovery of BA.4 and BA.5 variants-infected cases is still rare in Indonesia, the global transmission of these two variants is already widespread.

Quoting the Global Initiative on Sharing All Influenza Data (GISAID) report, Health Ministry spokesperson Mohammad Syahril said the transmission of BA.4 or BA.5 was faster than the Omicron BA.1 and BA.2 subvariants. However, there was no indication that those variants caused more severe pain than other Omicron variants.

Are the BA.4 and BA.5 subvariants causing the increase in positive cases of Covid-19 globally?

In South Africa, Portugal and Chile, the increase in Covid-19 cases have been blamed on BA.4 and BA.5 subvariants. So has the increasing caseload in Indonesia, as Health Minister Budi Gunadi Sadikin confirmed, based on the finding of the infection of the two subvariants. The health minister said these new subvariants had the capacity of escaping immunity, meaning that they are able to breach the human immune system, either acquired from vaccination or from ingrown immunity.


Viral mutation

While the subvariants are known to transmit more rapidly, it is still unknown how widely they are currently spreading. In Africa, Omicron’s BA.4 and BA.5 variants have increased dramatically since March, accounting for 16 percent of the prevalence of new cases. In South Africa, these variants dominated cases during April (73 percent) and May (94 percent). Meanwhile, Delta variant infection cases in Africa are still detected, though in low frequency.

Despite triggering new outbreak of cases, the BA.4 and BA.5 subvariants are not categorized as variants of concern (VOC) because these two subvariants are still within the lineage of the Omicron variant. BA.4 and BA.5 share the mutating characteristics of their parent variant (Omicron), but they are more similar to the BA.2 subvariant.

Their spike protein, which has a structure in the form of tendrils that stick to the sphere-shaped virus body), is similar to the BA.2 strain, the difference being they undergo a deletion of the 69-70th amino acid, or the deletion of one amino acid.

As a result, some polymerase chain reaction (PCR) testing tools, such as the Thermo Fisher Scientific TaqPath commonly used to detect the Omicron BA.1 variant, sometimes fail to detect the BA.4 and BA.5 subvariants (Everatt, 2022).

What have also drawn experts ’attention are the unique mutation changes called L452R, F486V and Q493 in BA.4 and BA.5. These two new subvariants have exactly the same mutation in the spike protein, but in several other areas of transmission, other forms of mutation have been found, apart from the spike protein changes. As with the previous variants, the spike protein in the form of tendrils is what causes the infection by clinging to human cells.


Because the spike protein structure is the same, these two BA.4 and BA.5 subvariants can be said to be identical.

According to Tchesnokova et al, the L452R mutation is a change in the amino acid from Leucine to Arginine, at the 452nd point of the spike protein. The spike protein of this virus is composed of 1,273 amino acids, and 319 to 541 are the amino acid coding region for the receptor binding domain (RBD) to allow the virus to bind to receptors in the human body (ACE-2 receptor). Mutations that occur in the 452nd amino acid coding region cause significant changes in characteristics.

As we know, the Covid-19 virus is not a living creature, but a collection of proteins that can only replicate to damage the targeted cells when inside the host's body. Changes in the amino acids that make up this protein allow changes in the characteristics of this virus.

In the L452R mutation, the virus has the ability to escape the antibody shield acquired from vaccination or ingrown immunity due to previous illness exposure. The L452R mutation also makes this virus more easily cling to the human cells, hence increasing its capacity to spread, infect and ultimately damage infected cells.

The L452R mutation was first detected in the Epsilon B.1.427/B.1.429 variant found in California, from November to December 2020. However, the mutation became notorious after being associated with the mutation in the Delta variant.

Such a type of mutations did not occur in its predecessor variant, namely Omicron BA.2, so it can be said that the L453R mutation results in more rapid changes in characteristics of the BA.4 and BA.5 subvariants. The L452R mutation has also been found in other variants, such as Delta, Epsilon and Kappa.

Based on the location of other dominant mutations, it is reported that other changes occur due to the F486V mutation located close to the spike protein, thus helping the virus avoid destruction by the human immune system. This mutation occurs in the amino acid at the 486th region of Phenylalanine, which changes to Valine, hence called F486V.

Uniquely, this mutation is very scarce and rarely found in the previous variant-triggered outbreaks. The mutation at this region occurred in the Cluster 5 variant pandemic that was found in minks in Denmark in December 2020. It was an F486L mutation (a mutation of the amino acid Phenylalanine at region 486 to Leucine). The mutations in BA.4 and BA.5 that see the amino acid changing to Valine have significantly more ability to escape from binding by human antibodies.

Another mutation found in these two subvariants is R493Q. However, this mutation in the RBD region weakens the virus infecting ability. What’s concerning most about this subvariants is the change in amino acid deletion at regions 69-70, which makes the PCR test unable to read the S-gene. Therefore, the detection of these subvariants requires more reliable technology and extra precautionary measures.

As described above, these subvariants carry antibody escape capacity. In addition, as happens with each emergence of a new mutation, these subvariants also spread quickly.

Since it was first detected on June 6, with the infection of four people, these subvariants spread quickly with the number of infected people amounting to 20 in a few days. The number was relatively low if compared with the transmission in other countries. GISAID reported that in January and February this year, the BA.4 subvariant has been detected in 6,903 gnome sequences in 58 countries as of June 10, the most cases being in South Africa, the United States, the United Kingdom, Denmark and Israel. As for the BA.5 subvariant, 8,687 gnome sequences were detected in 63 countries, the most of which were in the US, Portugal, Germany, the UK and South Africa.

The European Center for Disease Prevention and Control (ECDC) had initially classified BA.4 and BA.5 as a variant of interest (VOI) or variant under monitoring before upgrading the classification to variant of concern (VOC) on 12 May due to their worrying transmission speed. How these subvariants potentially threaten Indonesia, according to World Health Organization’s (WHO) former director for infectious diseases for Southeast Asia, Tjandra Yoga Aditama, will depend on several factors, such as immunity protection, coverage and timing of vaccinations, as well as the landscape of the past transmission wave.

In general, there is no evidence that these new subvariants pose more severe infections, but caution deserves priority over potential increases in hospitalization and intensive care unit (ICU) treatment in those aged over 60 or 65 years. Experts are still collecting data related to the effectiveness of monoclonal antibodies (mAb) drugs on BA.4 and BA.5.

In Singapore, these subvariants have been blamed for a 23 percent increase in weekly cases. While the BA.2 subvariant is still dominant, the distribution of the new subvariants has increased rapidly. As reported on the website of Singapore’s Health Ministry, the island state recorded 7,109 new cases on 21 June, which was double the previous day's 3,220 cases. As much as 92 percent of Singaporeans have now received the full dose of the Covid-19 vaccine, and 77 percent have taken booster jabs.

The CDC estimates that the BA.4 and BA.5 variants, which initially only accounted for about 1 percent of total cases in the world until mid-June, have grown to 22 percent of the total cases. This is because the variants of interest, or the variants under close surveillance, can spread more quickly and breach the immune defenses built by previous infections or by virtue of vaccination. It means a person can be re-infected even if they have been infected with the Omicron variant before.


Caseload in Indonesia

The Indonesian Health ministry office estimates that cases of the Omicron BA.4 and BA.5 subvariants in Indonesia may spike in the second or third week of July. Basically, the wave of new mutation variants will usually peak around one month after the first case was discovered. Given the data from abroad, we must heighten our vigilance.

Attention shall be given more to vulnerable and at-risk groups, as well as those who may experience a decreasing antibodies, such as the elderly who have not received a booster vaccine or other groups of citizens who have not received vaccinations at all because of certain diseases. Health workers who received booster vaccines more than six months ago could also be experiencing a decrease in antibodies.

The government needs to tighten supervision on health protocols, the implementation of which have been very loose since the permitted Idul Fitri’s long homecoming holidays last May. It is now becoming more common to see people interacting without face masks. We should return to health protocols in anticipation for an increase in cases potentially sparked by the new subvariants. In so doing, we are preventing new variant infections from spiking.


Djoko Santoso
Professor of Medicine, Airlangga University;
Chair of the East Java Indonesian Ulema Council (MUI) Health Board

This article was translated by Musthofid.